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NDA 211964 Viloxazine extended-release capsules

Integrated Review Table 1. Administrative Application Information Category Application Information Application type NDA Application number(s) 211964 Priority or standard Standard Submit date(s) 11/8/2019 Received date(s) 11/8/2019 PDUFA goal date 11/8/2020 Division/office Division of Psychiatry Products (DPP) Review completion date 7/8/2020 Established name Viloxazine hydrochloride (Proposed) trade name Qelbree Pharmacologic class Code name SPN-812 Applicant Supernus Pharmaceuticals, Inc. Dose form/formulation(s) Extended-release capsules Dosing regimen Patients ages 6-11 years: 100 mg to 400 mg once daily Patients ages 12-17 years: 200 mg to 400 mg once daily Applicant proposed Attention deficit hyperactivity disorder (ADHD) indication(s)/population(s) Proposed SNOMED Attention deficit hyperactivity disorder indication Regulatory action Complete response Approved Treatment of attention deficit hyperactivity disorder in pediatric indication(s)/population(s) patients 6 to 17 years of age (if applicable) Approved SNOMED Attention deficit hyperactivity disorder indication

Integrated Review Template, version date 2019/10/16

Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

Table of Contents Table of Tables ...... 1 Table of Figures ...... 10 Glossary ...... 12 I. Executive Summary ...... 14 1. Summary of Regulatory Action ...... 14 2. Benefit-Risk Assessment ...... 16 II. Interdisciplinary Assessment ...... 21 3. Introduction ...... 21 3.1. Review Issue List ...... 22 3.2. Approach to the Review ...... 23 4. Patient Experience Data ...... 26 5. Pharmacologic Activity, , and Clinical ...... 27 5.1. Nonclinical Assessment of Potential Effectiveness ...... 29 6. Assessment of Effectiveness ...... 29 6.1. Dose and Dose Responsiveness ...... 29 6.2. Clinical Trials Intended to Demonstrate Efficacy ...... 30 6.2.1. Trial Design ...... 30 6.2.2. Eligibility Criteria ...... 31 6.2.3. Statistical Analysis Plan ...... 32 6.2.4. Results of Analyses of Clinical Trials/Studies Intended to Demonstrate Efficacy ...... 33 6.2.4.1. Study 301 ...... 37 6.2.4.2. Study 302 ...... 41 6.2.4.3. Study 303 ...... 46 6.2.4.4. Study 304 ...... 50 6.2.5. Integrated Assessment of Effectiveness ...... 54 6.3. Key Review Issues Relevant to the Evaluation of Benefit ...... 54 (b) (4) 6.3.1...... 54 6.4. Potential Risks or Safety Concerns Based on or Other Drug- Specific Factors ...... 59 7. Risk and Risk Management ...... 59 7.1. Potential Risks or Safety Concerns Based on Nonclinical Data ...... 59

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

7.2. Potential Safety Concerns Identified Through Postmarket Experience ...... 61 7.3. FDA Approach to the Safety Review ...... 66 7.4. Adequacy of the Clinical Safety Database ...... 66 7.5. Safety Findings and Safety Concerns Based on Review of the Clinical Safety Database ...... 68 7.5.1. Overall Adverse Event Summary ...... 68 7.5.2. Deaths ...... 69 7.5.3. Dropouts and/or Discontinuations Due to Adverse Events ...... 73 7.5.4. Treatment-Emergent Adverse Events ...... 78 7.5.5. Laboratory Findings ...... 81 7.6. Key Review Issues Relevant to the Evaluation of Risk ...... 82 7.6.1. Risk of ...... 82 7.6.2. Risk of Suicidal Ideation and Behavior ...... 87 7.6.3. Risk of Negative Effects on Weight and Growth ...... 90 7.6.4. Risk of Heart Rate and Blood Pressure Changes ...... 95 7.6.5. Risk of Liver Injury ...... 108 8. Therapeutic Individualization ...... 118 8.1. Intrinsic Factors ...... 118 8.2. Drug Interactions ...... 119 8.3. Plans for Pediatric Drug Development ...... 120 8.4. Pregnancy and Lactation ...... 121 9. Product Quality ...... 123 9.1. Device or Combination Product Considerations ...... 123 10. Human Subjects Protections/Clinical Site and Other GCP Inspections/Financial Disclosure ...... 123 11. Advisory Committee Summary ...... 124 III. Appendices ...... 125 12. Summary of Regulatory History ...... 125 13. Pharmacology Toxicology: Assessments and Additional Information ...... 126 13.1. Summary Review of Studies Submitted Under IND ...... 126 13.2. Individual Reviews of Studies Submitted to the NDA ...... 127 13.2.1. Drug Impurities and Excipients ...... 127 13.2.1.1. Impurities ...... 127

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

13.2.1.2. Excipients ...... 128 13.2.2. Pharmacology ...... 128 13.2.2.1. Primary Pharmacology ...... 128 13.2.2.2. Secondary Pharmacology ...... 130 13.2.2.3. Safety Pharmacology ...... 130 13.2.3. Pharmacokinetics/ADME ...... 131 13.2.3.1. Absorption and Distribution ...... 131 13.2.3.2. and ...... 132 13.2.3.3. Drug-Drug Interactions ...... 136 13.2.4. General Toxicology ...... 137 13.2.4.1. Single-dose Toxicity ...... 137 13.2.4.2. Repeat-dose Toxicity ...... 137 13.2.5. Genetic Toxicology ...... 163 13.2.5.1. In Vitro Reverse Mutation Assay in Bacterial Cells (Ames) ...... 163 13.2.5.2. In Vitro Assays in Mammalian Cells ...... 164 13.2.5.3. In Vivo Clastogenicity Assay in Rodent (Bone Marrow Micronucleus Assay) ...... 166 13.2.6. Carcinogenicity Study ...... 166 13.2.6.1. Two-year Oral Gavage Carcinogenicity Study of Viloxazine in Wistar Rats ...... 166 13.2.6.2. Twenty-six-Week Oral Gavage Carcinogenicity Study With Viloxazine in Transgenic rasH2 Mice ...... 171 13.2.7. Reproductive and Developmental Toxicology...... 176 13.2.7.1. Male and Female Fertility Study ...... 176 13.2.7.2. Embryofetal-Developmental Toxicity Study ...... 180 13.2.7.3. Pre- and Post-natal Developmental Toxicity ...... 188 13.2.7.4. Juvenile Animal Study ...... 196 13.2.8. Phototoxicity ...... 201 14. Clinical Pharmacology Assessment: Additional Information ...... 201 14.1. In Vitro Studies ...... 201 14.2. Bioanalytical Analysis ...... 204 14.3. In Vivo Studies ...... 205 14.3.1. ADME Studies ...... 205

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

14.3.2. Drug-Drug Interactions ...... 208 14.3.3. Intrinsic Factors ...... 213 14.4. Pharmacometrics Review ...... 215 14.4.1. Executive Summary ...... 215 14.4.2. Applicant’s Analysis ...... 215 14.4.3. Reviewer’s Analysis ...... 217 15. Trial Design: Additional Information and Assessment ...... 221 16. Efficacy Assessment Additional Information and Assessment ...... 231 16.1. Gender, Race, Age ...... 231 16.2. Other Special/Subgroup Populations: U.S. versus Non-U.S...... 235 16.3. Graphical Exploration of Missing Data Patterns ...... 236 17. Clinical Safety Assessment Additional Information and Assessment ...... 239 18. Mechanism of Action/Drug Resistance Additional Information and Assessment ...... 269 19. Other Drug Development Considerations Additional Information ...... 269 20. Data Integrity-Related Consults (OSI, Other Inspections) ...... 269 21. Labeling Summary of Considerations and Key Additional Information ...... 269 22. Postmarketing Requirements and Commitments ...... 272 23. Financial Disclosure ...... 273 24. References ...... 274 25. Review Team ...... 275

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

Table of Tables Table 1. Administrative Application Information ...... i Table 2. Benefit-Risk Framework ...... 16 Table 3. Clinical Trials Submitted in Support of Efficacy and Safety Determinations1 for Viloxazine Extended-Release ...... 24 Table 4. Patient Experience Data Submitted or Considered ...... 26 Table 5. Summary of General Clinical Pharmacology and Pharmacokinetics ...... 27 Table 6. Baseline Demographic Characteristics, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) ...... 34 Table 7. Patient Screening and Randomization (Studies 812P301, 812P302, 812P303, and 812P304) ...... 35 Table 8. Patient Disposition (Studies 812P301, 812P302, 812P303, and 812P304) ...... 36 Table 9. Change from Baseline at Week 6 (EOS) in ADHD-RS-5 Total Score (ITT; MMRM) (Study 301) ...... 38 Table 10. Observed Global Severity Score (CGI-S) at Baseline and Observed Global Improvement Score (CGI-I) at Week 6 (EOS)–(ITT; ANCOVA) (Study 301) ...... 39 Table 11. Change from Baseline at Week 6 (EOS) in the Conners 3-Parent Report Composite T-Score–(ITT; ANCOVA) (Study 301) ...... 39 Table 12. Change from Baseline at Week 6 (EOS) in WFIRS-P Total Average Score– Key Secondary Analysis–(ITT; ANCOVA) (Study 301) ...... 40 Table 13. Change from Baseline at Week 6 (EOS) in ADHD-RS-5 Total Score (ITT; MMRM) (Study 302) ...... 42 Table 14. Observed Global Severity Score (CGI-S) at Baseline and Observed Global Improvement Score (CGI-I) at Week 6 (EOS), (ITT; ANCOVA) (Study 302) ...... 43 Table 15. Change from Baseline at Week 6 (EOS) in the Conners 3-Parent Report Composite T-Score, (ITT; ANCOVA) (Study 302) ...... 43 Table 16. Change from Baseline at Week 6 (EOS) in WFIRS-P Total Average Score– Key Secondary Analysis, (ITT; ANCOVA) (Study 302) ...... 44 Table 17. Change from Baseline at Week 8 (EOS) in ADHD-RS-5 Total Score (ITT; MMRM) (Study 303) ...... 46 Table 18. Observed Global Severity Score (CGI-S) at Baseline and Observed Global Improvement Score (CGI-I) at Week 8 (EOS), (ITT; ANCOVA) (Study 303) ...... 48 Table 19. Change from Baseline at Week 8 (EOS) in the Conners 3–Parent Report Composite T-Score, (ITT; ANCOVA) (Study 303) ...... 48 Table 20. Change from Baseline at Week 8 (EOS) in WFIRS-P Total Average Score– Key Secondary Analysis, (ITT; ANCOVA) (Study 303) ...... 48

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

Table 21. Change from Baseline at Week 7 (EOS) in ADHD-RS-5 Total Score (ITT; MMRM) (Study 304) ...... 51 Table 22. Observed CGI-S at Baseline and Observed CGI-I at Week 8 (EOS), (ITT; ANCOVA) (Study 304) ...... 52 Table 23. Change from Baseline at Week 8 (EOS) in the Conners 3-Parent Report Composite T-Score, (ITT; ANCOVA) (Study 304) ...... 52 Table 24. Change from Baseline at Week 8 (EOS) in WFIRS-P Total Average Score– Key Secondary Analysis, (ITT; ANCOVA) (Study 304) ...... 53 Table 25. Number of Subjects within Each Treatment Group Categorized by Age Group and Weight (Study 812P304)...... 57 Table 26. Dose-Related Adverse Events (Studies 812P301, 812P302, 812P303, and 812P304) ...... 58 Table 27. Heart Rate and Blood Pressure Assessments (Study 812P304) ...... 58 Table 28. Duration of Exposure, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) ...... 67 Table 29. Duration of Exposure to Viloxazine ER ...... 68 Table 30. Overview of Adverse Events, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) ...... 69 Table 31. Serious Adverse Events, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) ...... 70 Table 32. Serious Adverse Events (Study 812P310) ...... 71 Table 33. Adverse Events Leading to Discontinuation, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304)...... 74 Table 34. FDA MedDRA Queries (Narrow) Leading to Discontinuation, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) ...... 75 Table 35. Adverse Events1 Occurring at ≥2% and at a Higher Frequency in the Treatment Arm than the Comparator Arm, Phase 3 Safety Population ...... 79 Table 36. FDA MedDRA Queries1 Occurring at ≥2% and at a Higher Frequency in the Treatment Arm than the Comparator Arm, Phase 3 Safety Population ...... 80 Table 37. Liver Transaminases, Shifts from Normal to Elevated at End of Study Visit, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) ...... 82 Table 38. Summary of Viloxazine-Related Convulsion and CNS Findings in Nonclinical Studies ...... 82 Table 39. Patients Reporting Suicidal Ideation as an Adverse Event After Viloxazine ER Exposure–Phase 2 and Phase 3 Studies ...... 88 Table 40. Percentage of Patients With a ≥7% Decrease in Body Weight, Phase 3 Placebo-Controlled Trials ...... 93 Table 41. Growth Parameters from Baseline to Month 12 (Study 812P310) ...... 94 2 Integrated Review Template, version date 2019/10/16

Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

Table 42. Mean Change in Heart Rate (Study 812P301) ...... 97 Table 43. Mean Change in Heart Rate (Study 812P302) ...... 97 Table 44. Mean Change in Heart Rate (Study 812P303) ...... 97 Table 45. Mean Change in Heart Rate (Study 812P304) ...... 97 Table 46. Heart Rate Out-of-Range (Study 812P301) ...... 98 Table 47. Heart Rate Out-of-Range (Study 812P303) ...... 98 Table 48. Heart Rate Out-of-Range (Study 812P302) ...... 98 Table 49. Heart Rate Out-of-Range (Study 812P304) ...... 98 Table 50. Patients in Phase 3 Controlled Studies with a ≥15 BPM Increase in Heart Rate at EOS ...... 99 Table 51. Patients in Phase 3 Controlled Studies with a ≥25 BPM Increase in Heart Rate at EOS ...... 99 Table 52. Mean Change from Baseline in Systolic Blood Pressure (Study 812P301) ....100 Table 53. Mean Change from Baseline in Systolic Blood Pressure (Study 812P302) ....100 Table 54. Mean Change from Baseline in Systolic Blood Pressure (Study 812P303) ....100 Table 55. Mean Change from Baseline in Systolic Blood Pressure (Study 812P304) ....100 Table 56. Systolic Blood Pressure Out-of-Range (Study 812P301) ...... 101 Table 57. Systolic Blood Pressure Out-of-Range (Study 812P303) ...... 101 Table 58. Systolic Blood Pressure Out-of-Range (Study 812P302) ...... 101 Table 59. Systolic Blood Pressure Out-of-Range (Study 812P304) ...... 101 Table 60. Patients with a ≥10 mmHg Change in Systolic Blood Pressure at EOS ...... 102 Table 61. Patients with a ≥20 mmHg Change in Systolic Blood Pressure at EOS ...... 102 Table 62. Mean Change from Baseline in Diastolic Blood Pressure (Study 812P301) ..102 Table 63. Mean Change from Baseline in Diastolic Blood Pressure (Study 812P302) ..103 Table 64. Mean Change from Baseline in Diastolic Blood Pressure (Study 812P303) ..103 Table 65. Mean Change from Baseline in Diastolic Blood Pressure (Study 812P304) ..103 Table 66. Diastolic Blood Pressure Out-of-Range (Study 812P301) ...... 104 Table 67. Diastolic Blood Pressure Out-of-Range (Study 812P303) ...... 104 Table 68. Diastolic Blood Pressure Out-of-Range (Study 812P302) ...... 104 Table 69. Diastolic Blood Pressure Out-of-Range (Study 812P304) ...... 105 Table 70. Patients with a ≥10 mmHg Change in Diastolic Blood Pressure at EOS ...... 105 Table 71. Patients with a ≥20 mmHg Change in Diastolic Blood Pressure at EOS ...... 105 Table 72. Vital Signs by Visit, Safety Population (Study 812P310) ...... 106

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

Table 73. Change from Baseline to Month 12 in Heart Rate (Study 812P310) ...... 107 Table 74. Change from Baseline to Month 12 in Systolic Blood Pressure (Study 812P310) ...... 107 Table 75. Change from Baseline to Month 12 in Diastolic Blood Pressure (Study 812P310) ...... 107 Table 76. Viloxazine-Related Liver Findings in Nonclinical Species and Corresponding Exposure Multiples ...... 109 Table 77. Hepatobiliary Assessments (Study 812P301) ...... 110 Table 78. Hepatobiliary Assessments (Study 812P302) ...... 110 Table 79. Hepatobiliary Assessments (Study 812P303) ...... 111 Table 80. Hepatobiliary Assessments (Study 812P304) ...... 112 Table 81. Out-of-Range Hepatobiliary Assessments (Study 812P301)...... 113 Table 82. Out-of-Range Hepatobiliary Assessments (Study 812P302)...... 113 Table 83. Out-of-Range Hepatobiliary Assessments (Study 812P303)...... 114 Table 84. Out-of-Range Hepatobiliary Assessments (Study 812P304)...... 114 Table 85. Number of Subjects with Abnormal Liver and Liver Function Tests (Studies 812P202, 812P301, 812P302, 812P303, and 812P304) ...... 116 Table 86. Clinical Site Inspections (Studies 812P301, 812P302, 812P303, and 812P304) ...... 123 Table 87. Summary of the Pharmacological Activity of Viloxazine at Various Receptors and Transporters ...... 129 Table 88. In Vitro of Viloxazine in Human, Rat, and Dog ...... 132 Table 89. In Vitro of [14C]-Viloxazine Formed in Rat, Dog, and Human Hepatocytes after a 120-Minute Incubation ...... 132 Table 90. Summary of Drug-Related Components in Human Plasma ...... 135 Table 91. Relative Levels of Glucuronidated 5-Hydroxy-Viloxazine in Human and Rat ...... 136 Table 92. Methods for A 13-Week Oral Gavage Toxicity and Toxicokinetic Study of SPN-809V in Sprague Dawley Rats with a 4-Week Recovery Period ...... 138 Table 93. Histopathology Findings in the Liver at the Terminal Necropsy from the 13-Week Rat Study ...... 141 Table 94. Toxicokinetic Parameters of Viloxazine in the 13-Week Rat Study ...... 141 Table 95. An 18-Month Chronic Oral Toxicity in Rats Methods ...... 142 Table 96. Drug-Related Centrilobular Vacuolation (Lipid Accumulation) at the 6- Month Interim Analysis in the 18-Month Rat Study ...... 146

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

Table 97. Drug-Related Histopathology Changes at the Terminal and Recovery Necropsies in the 18-Month Rat Study ...... 146 Table 98. Incidence of Hepatocellular Fat Droplets at the Terminal and Recovery Necropsies in the 18-Month Rat Study ...... 147 Table 99. A 4-Week Oral Gavage Toxicity and Toxicokinetic Study with Viloxazine in rasH2 Transgenic Wild-Type Mice with 2-Week Recovery Methods ...... 149 Table 100. Drug-Related Clinical Signs in the 4-Week Mouse Study ...... 150 Table 101. Drug-Related Histopathology Changes in the Liver in the 4-Week Mouse Study ...... 151 Table 102. Toxicokinetic Parameters of Viloxazine in the 4-Week Mouse Study ...... 152 Table 103. A 13-Week Oral (Capsule) Toxicity and Toxicokinetics Study of SPN- 809V in Beagle Dogs with a 4-Week Recovery Period Methods ...... 153 Table 104. QTc Interval at the End of the Treatment Period in the 13-Week Dog Study ...... 155 Table 105. Toxicokinetic Parameters of Viloxazine in the 13-Week Dog Study ...... 157 Table 106. Viloxazine Hydrochloride: A 12-Month Oral Toxicity Study in Dogs Methods...... 158 Table 107. Drug-Related Gross Pathology Changes in the Liver at the Terminal Necropsy in the 12-Month Dog Study ...... 159 Table 108. Drug-Related Histopathology Changes in the Liver at the Terminal Necropsy in the 12-Month Dog Study ...... 161 Table 109. Salmonella-Escherichia coli/Mammalian-Microsome Reverse Mutation Assay with a Confirmatory Assay Methods ...... 163 Table 110. Chromosomal Aberrations in Cultured Human Peripheral Blood Lymphocytes Methods ...... 165 Table 111. Methods for Study 812V-Tox2014-002 ...... 167 Table 112. Tumor Types with P-Values ≤0.05 for Pairwise Comparisons between the Treatment and Control Groups in the 2-Year Rat Carcinogenicity Study ...... 170 Table 113. TK Parameters of Viloxazine in the 2-Year Rat Carcinogenicity Study ...... 171 Table 114. Methods for 812V-Tox2016-002 ...... 172 Table 115. Summary of Body Weight and Cumulative Weight Gain at the End of the Treatment Period in the 26-Week Carcinogenicity Study in Tg.rasH2 Mice ...... 173 Table 116. Thymic Involution in the 26-Week Carcinogenicity Study in Tg.rasH2 Mice ...... 175 Table 117. Summary of Viloxazine TK Parameters in the 26-Week Carcinogenicity Study in Tg.rasH2 Mice ...... 176

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

Table 118. Viloxazine Hydrochloride: A Fertility and Reproductive Performance Study in Rat Methods...... 177 Table 119. Male and Female Fertility Index in the Rat Fertility Study ...... 178 Table 120. Drug-Related Decreases in Offspring Viability/Lactation Index in the Rat Fertility Study ...... 179 Table 121. Drug-Related Decreases in Offspring Body Weight in the Rat Fertility Study ...... 179 Table 122. Plasma Levels of Viloxazine in Pups on Lactation Day 4 ...... 180 Table 123. Plasma Levels of Viloxazine in Pups on Lactation Day 21 ...... 180 Table 124. Viloxazine Hydrochloride: A Teratogenic Potential Study in Rats–Oral Methods...... 181 Table 125. Drug-Related Changes in Cesarean Parameters in the Rat Embryo-Fetal Developmental Toxicity Study ...... 182 Table 126. Drug-Related External Fetal Observations in the Rat Embryo-Fetal Developmental Toxicity Study ...... 183 Table 127. Visceral Fetal Findings in the Rat Embryo-Fetal Developmental Toxicity Study ...... 184 Table 128. Study of Effects of Orally Administered Viloxazine on Embryofetal Developmental Toxicity in New Zealand White Rabbits Methods ...... 184 Table 129. Drug-Related Decreased in Body Weight Gain in the Rabbit Embryo-Fetal Developmental Toxicity Study ...... 186 Table 130. Toxicokinetic Parameters of Viloxazine in the Rabbit Embryo-Fetal Developmental Toxicity Study ...... 187 Table 131. Study of Effects of Orally Administered Viloxazine on Pre- and Post-natal Development, Including Maternal Function in Wistar Rats Methods ...... 189 Table 132. Drug-Related Premature Deaths in the Rat Pre- and Post-natal Developmental Toxicity Study ...... 190 Table 133. Drug-Related Decreases in Maternal Body Weight, Weight Gain, and Food Consumption in the Rat Pre- and Post-natal Developmental Toxicity Study ..190 Table 134. Drug-Related Decreases in Offspring Survivability in the Rat Pre- and Post-natal Developmental Toxicity Study ...... 191 Table 135. Drug-related Delay in Offspring Growth and Development in the Rat Pre- and Post-natal Developmental Toxicity Study ...... 192 Table 136. Toxicokinetic Parameters of Viloxazine in the Rat Pre- and Post-natal Developmental Toxicity Study ...... 194 Table 137. 8-Week Oral Rat Juvenile Toxicity and Toxicokinetic Study with Recovery Evaluation Methods ...... 196

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

Table 138. Summary Toxicokinetic Parameters of Viloxazine in the Juvenile Rat Study ...... 201 Table 139. SPN-812 (Viloxazine) Pharmacokinetic Parameters after a Single Dose on Day 1, Mean ± SD (%CV) ...... 206 Table 140. SPN-812 (Viloxazine) Steady-State Pharmacokinetic Parameters on Day 6 after Multiple Doses, Mean ± SD ...... 207 Table 141. Viloxazine Steady-State Relative Following Administration of SPN-812 ER vs. IR ...... 207 Table 142. Effect of Food on Viloxazine (SPN-812) ...... 208 Table 143. Statistical Analysis of and Its () Pharmacokinetic Parameters Following Administration of MCC Alone and Coadministration with Viloxazine ER ...... 209 Table 144. Statistical Analysis of and Its Metabolite () Pharmacokinetic Parameters Following Administration of MCC Alone and Coadministration with Viloxazine ER ...... 209 Table 145. Statistical Analysis of Midazolam and Its Metabolite (1- Hydroxymidazolam) Pharmacokinetic Parameters Following Administration of MCC Alone and Coadministration with Viloxazine ER ...... 210 Table 146. Statistical Analysis of d- Pharmacokinetic Parameters Following Administration of Vyvanse Alone (Treatment A) and Coadministration with Viloxazine ER (Treatment C) ...... 211 Table 147. Statistical Analysis of Pharmacokinetic Parameters Following Administration of Concerta Alone (Treatment A) and Coadministration with Viloxazine ER (Treatment C) ...... 211 Table 148. Statistical Analysis of Viloxazine Pharmacokinetic Parameters Following Administration of Viloxazine ER Alone (Treatment B) and Coadministration with Vyvanse (Treatment C) ...... 212 Table 149. Statistical Analysis of Viloxazine Pharmacokinetic Parameters Following Coadministration of Viloxazine ER and Concerta ...... 212 Table 150. Statistical Analysis of Viloxazine Pharmacokinetic Parameters Following Administration of Viloxazine ER with ...... 213 Table 151. Summary of Viloxazine Pharmacokinetics After Single-Dose Administration to Subjects with Mild, Moderate, and Severe Renal Impairment and Matched Normal-Renal-Function Controls ...... 214 Table 152. Summary of Viloxazine PK in CYP2D6 Poor Metabolizers and Extensive Metabolizers Following Multiple, Once-Daily Doses of 900 mg Viloxazine ER .....215 Table 153. Parameter Estimates of the Applicant’s Final PPK Model ...... 216

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

Table 154. Estimated Viloxazine and Metabolite PK Parameters (Cmax and AUC0-24) at Steady-State in Children and Adolescents at Doses of 100, 200, 400, and 600 mg ...... 219 Table 155. Schedule of Assessments (Study 812P301) ...... 226 Table 156. Study 301 Subgroup Analysis by Race: ADHD-RS-5 Total Score (ITT) .....231 Table 157. Study 301 Subgroup Analysis by Gender: ADHD-RS-5 Total Score (ITT) .232 Table 158. Study 301 Subgroup Analysis by Age: ADHD-RS-5 Total Score (ITT) ...... 232 Table 159. Study 302 Subgroup Analysis by Race: ADHD-RS-5 Total Score (ITT) .....232 Table 160. Study 302 Subgroup Analysis by Gender: ADHD-RS-5 Total Score (ITT) .233 Table 161. Study 302 Subgroup Analysis by Age: ADHD-RS-5 Total Score (ITT) ...... 233 Table 162. Study 303 Subgroup Analysis by Race: ADHD-RS-5 Total Score (ITT) .....233 Table 163. Study 303 Subgroup Analysis by Gender: ADHD-RS-5 Total Score (ITT) .234 Table 164. Study 303 Subgroup Analysis by Age: ADHD-RS-5 Total Score (ITT) ...... 234 Table 165. Study 304 Subgroup Analysis by Race: ADHD-RS-5 Total Score (ITT) .....234 Table 166. Study 304 Subgroup Analysis by Gender: ADHD-RS-5 Total Score (ITT) .235 Table 167. Study 304 Subgroup Analysis by Age: ADHD-RS-5 Total Score (ITT) ...... 235 Table 168. Adverse Events With Grouped Terms, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304)...... 241 Table 169. Adverse Reactions in ≥2% of Viloxazine ER–Treated Patients (More Frequently than Placebo) in Phase 3 Placebo-Controlled Trials ...... 242 Table 170. Adverse Events by System Organ Class, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304)...... 243 Table 171. Psychiatric Adverse Events in ≥3 Patients Ages 6 to 11 Years in Phase 3 Studies and at a Frequency Greater than in Placebo-Treated Patients ...... 245 Table 172. Psychiatric Adverse Events Occurring in ≥3 Patients Ages 12 to 17 Years in Phase 3 Trials and at a Frequency Greater than in Placebo-Treated Patients ...... 245 Table 173. Psychiatric Adverse Events Occurring in ≥2 Patients in Study 812P202 ...... 246 Table 174. Adverse Events Leading to Discontinuation, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304)...... 247 Table 175. Laboratory Reference Ranges-Patients Ages 6 to 11 Years ...... 251 Table 176. Laboratory Reference Ranges-Patients Ages 12 to 17 Years ...... 251 Table 177. Laboratory Values1 (Study 812P301) ...... 251 Table 178. Laboratory Values1 (Study 812P302) ...... 253 Table 179. Laboratory Values1 (Study 812P303) ...... 255 Table 180. Laboratory Values1 (Study 812P304) ...... 257

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

Table 181. Laboratory Parameters by Visit, Safety Population (Study 812P310) ...... 259 Table 182. Electrocardiogram Values1 (Study 812P301) ...... 260 Table 183. Electrocardiogram Values1 (Study 812P302) ...... 261 Table 184. Electrocardiogram Values1 (Study 812P303) ...... 262 Table 185. Electrocardiogram Values1 (Study 812P304) ...... 263 Table 186. Shift from Normal to Prolonged QTcF (> 440) in Viloxazine ER–Exposed Patients (Studies 812P301, 812P302, 812P303, and 812P304) ...... 264 Table 187. Treatment-Emergent Adverse Events Occurring in ≥2% of Viloxazine- Treated Patients and More Frequently than Placebo (Study 812P202) ...... 264 Table 188. Adverse Events by Demographic Subgroup, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304)...... 265 Table 189. PK Parameters of Single Oral Doses of 200mg ER and IR Formulations of SPN812 ...... 268 Table 190. Covered Clinical Studies: 812P301, 812P302, 812P303, 812P304 ...... 273 Table 191. Reviewers of Interdisciplinary Assessment ...... 275 Table 192. Additional Reviewers of Application ...... 276 Table 193. Signatures of Reviewers ...... 276

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

Table of Figures Figure 1. Study 812P301–Study Schematic...... 31 Figure 2. LS Mean Change from Baseline in ADHD-RS-5 Total Score by Visit and Treatment Group (ITT) (Study 301) ...... 38 Figure 3. Percentage of Patients with a Specified Magnitude of ADHD-RS-5 Total Score Improvement at Week 6 (ITT) (Study 301) ...... 40 Figure 4. Percentage Response (ADHD-RS-5 Total Score) for Each Treatment Group at Week 6 by Response Threshold (ITT) (Study 301) ...... 41 Figure 5. LS Mean Change from Baseline in ADHD-RS-5 Total Score by Visit and Treatment Group (ITT) (Study 302) ...... 42 Figure 6. Percentage of Patients with a Specified Magnitude of ADHD-RS-5 Total Score Improvement at Week 6 (ITT) (Study 302) ...... 45 Figure 7. Percentage Response (ADHD-RS-5 Total Score) for Each Treatment Group at Week 6 by Response Threshold (ITT) (Study 302) ...... 45 Figure 8. LS Mean Change from Baseline in ADHD-RS-5 Total Score by Visit and Treatment Group (ITT) (Study 303) ...... 47 Figure 9. Percentage of Patients with a Specified Magnitude of ADHD-RS-5 Total Score Improvement at Week 8 (ITT) (Study 303) ...... 49 Figure 10. Percentage Response (ADHD-RS-5 Total Score) for Each Treatment Group at Week 8 by Response Threshold (ITT) (Study 303) ...... 50 Figure 11. LS Mean Change from Baseline in ADHD-RS-5 Total Score by Visit and Treatment Group (ITT) (Study 304) ...... 51 Figure 12. Percentage of Patients with a Specified Magnitude of ADHD-RS-5 Total Score Improvement at Week 7 (ITT) (Study 304) ...... 53 Figure 13. Percentage Response (ADHD-RS-5 Total Score) for Each Treatment Group at Week 7 by Response Threshold (ITT) (Study 304) ...... 54 Figure 14. Distribution of ADHD-RS-Total Score at the Last Visit (Studies 812P301, 812P302, 812P303, and 812P304) ...... 55 Figure 15. Findings from Band-Pass Filter Analysis (Study 812P304)...... 56 Figure 16. Efficacy Plot by Weight and Age Group (Study 812P304) ...... 57 Figure 17. Number of Individual Cases by Reaction Group–EudraVigilance Database ...63 Figure 18. Adverse Drug Reactions Reported to Vigibase–1976 to 2014 ...... 64 Figure 19. Suspected Adverse Reactions by Reaction Groups Reported to the FAERS Database–1997 to 2016 ...... 65 Figure 20. Mean Change in Weight from Baseline (Study 812P301) ...... 91 Figure 21. Mean Change in Weight from Baseline (Study 812P303) ...... 92 Figure 22. Mean Change in Weight from Baseline (Study 812P302) ...... 92 10 Integrated Review Template, version date 2019/10/16

Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

Figure 23. Mean Change in Weight from Baseline (Study 812P304) ...... 93 Figure 24. Effects of Intrinsic Factors on Viloxazine ...... 119 Figure 25. Effect of Viloxazine on Other Drugs ...... 120 Figure 26. Effects of d-Amphetamine and Methylphenidate on Viloxazine ...... 120 Figure 27. Metabolic Conversion of Viloxazine in Rat ...... 134 Figure 28. Drug-Related Decreases in Weight Gain and Food Consumption in the 18- Month Rat Study ...... 144 Figure 29. Drug-Related Decreases in Body Weight and Weight Gain during the Treatment Period in the 13-Week Dog Study ...... 155 Figure 30. Kaplan–Meier Survival Curves in the 2-Year Rat Carcinogenicity Study .....168 Figure 31. Body Weight Curve in the 2-Year Rat Carcinogenicity Study ...... 169 Figure 32. Drug-related Decreases in Body Weight and/or Weight Gain in the Juvenile Rat Study ...... 198 Figure 33. Drug-Drug Interaction Study Schematic ...... 208 Figure 34. Schematic Representation of the PK Model of Viloxazine ...... 216 Figure 35. Goodness-of-Fit Plots of the Applicant’s PPK Model for Viloxazine ...... 217 Figure 36. Body Weight PK Data of Subjects Dosed with 400 mg Viloxazine ...... 218 Figure 37. PK Data of Subjects Dosed with 400 mg Viloxazine by Sex ...... 220 Figure 38. PK Data of Subjects Dosed with Viloxazine by Race ...... 221 Figure 39. Study Design, 812P301 ...... 224 Figure 40. Study Design, 812P303 ...... 228 Figure 41. Study Design, 812P304 ...... 228 Figure 42. Study Design, 812P202 ...... 230 Figure 43. Missing Data Patterns (Study 301) ...... 236 Figure 44. Missing Data Patterns (Study 302) ...... 237 Figure 45. Missing Data Patterns (Study 303) ...... 238 Figure 46. Missing Data Patterns (Study 304) ...... 239 Figure 47. IRT for Cardiac Safety Studies Recommendations for Labeling Revisions ..266

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules Glossary

ADHD attention deficit hyperactivity disorder ADHD-RS ADHD Rating Scale ADME absorption, distribution, metabolism, excretion AE adverse event ALT alanine aminotransferase AST aspartate aminotransferase AUC area under the concentration-time curve BLA biologics license application BMI body mass index CAARS Conners’ Adult ADHD Rating Scale CDER Center for Drug Evaluation and Research CDTL cross-discipline team leader CFB change from baseline CGI-I Clinical Global Impression-Improvement CGI-S Clinical Global Impression-Severity Cmax maximum plasma concentration CMC chemistry, manufacturing, and controls CNS central nervous system CRO contract research organization CSA Controlled Substances Act CSS Controlled Substance Staff C-SSRS Columbia Suicide Severity Rating Scale CYP DA DARRTS Document Archiving, Reporting, and Regulatory Tracking System DP Division of Psychiatry DPMH Division of Pediatrics and Maternal Health DSM-5 Diagnostic and Statistical Manual of Mental Disorders-5 EC50 half maximal effective concentration ECG electrocardiogram EEG electroencephalogram eGFR estimated glomerular filtration rate EM extensive metabolizer EOS end of study ER extended-release FAERS FDA Adverse Event Reporting System FDA Food and Drug Administration FMQ FDA MedDRA Query GCP good clinical practice GD gestation day GLP good laboratory practice HD high dose IC50 half maximal inhibitory concentration ICH International Conference on Harmonisation

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IND investigational new drug ITT intent-to-treat IWRS interactive web response system LacD lactation day LC/MS/MS liquid chromatography-tandem mass spectrometry LD low dose LD50 median lethal dose LS least square MD mid dose MDRD Modification of Diet in Renal Disease MedDRA Medical Dictionary for Regulatory Activities MMRM mixed model repeated measures MNAR missing not at random MOA mechanism of action MRHD maximum recommended human dose MRI magnetic resonance imaging MTD maximum tolerated dose NDA new drug application NE norepinephrine NET norepinephrine transporter NOAEL no observed adverse effect level NOEL no observed effect level OPQ Office of Pharmaceutical Quality OSE Office of Surveillance and Epidemiology OSI Office of Scientific Investigation PK pharmacokinetic PM poor metabolizer PMR postmarketing requirement PND postnatal day QD once daily (Q)SAR quantitative structure-activity relationship REMS risk evaluation and mitigation strategy SAE serious adverse event SOC system organ class TEAE treatment-emergent adverse event Tmax time to maximum concentration TK toxicokinetic ULN upper limit of normal WFIRS-P Weiss Functional Impairment Rating Scale-Parent Report 5-HT

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

I. Executive Summary

1. Summary of Regulatory Action

Supernus Pharmaceuticals, Inc. (the Applicant) has submitted a 505(b)(1) new drug application (NDA) for viloxazine extended-release (ER) capsules for the treatment of attention deficit hyperactivity disorder (ADHD) in pediatric patients ages 6 to 17 years. Viloxazine is norepinephrine reuptake inhibitor that was marketed in Europe as an from the 1970s until 2008 (when it was withdrawn for commercial reasons). In the United States, viloxazine is a new molecular entity (NME) never previously approved or marketed for any indication. The Applicant submitted four randomized, placebo-controlled, double-blind studies in support of this NDA: 812P301, -302, -303, and -304. In subjects 6 to 11 years old, Study 301 (N=477) tested viloxazine ER 100 and 200 mg daily, and Study 303 (N=313) tested viloxazine ER 200 and 400 mg daily. In subjects 12 to 17 years old, Study 302 (N=310) tested viloxazine ER 200 and 400 mg daily, and Study 304 (N=297) tested viloxazine ER 400 and 600 mg daily. An open- label extension study, 812P310, provided long-term safety data. At the time of this review, Study 310 is ongoing, but there have been 687 exposures for at least 6 months and 347 exposures for at least 1 year; thus, ICH E1 guidelines have been satisfied. The Applicant’s development program provides substantial evidence of effectiveness for viloxazine for the treatment of ADHD in pediatric patients ages 6 to 17 years. Clinically meaningful improvements in ADHD symptoms were demonstrated for 100 mg, 200 mg, and 400 dosages of viloxazine ER in patients 6 to 11 years old, and for the 200 mg and 400 mg dosages of viloxazine ER in patients 12 to 17 years old. A 600 mg dosage of viloxazine ER was also tested in patients 12 to 17 years old. The 600 mg dosage was not shown to provide additional benefits, but is associated with a higher incidence of some adverse events (b) (4)

The key review issues associated with safety were evaluation of the risk of seizure, suicidal ideation and behavior (SI/B), weight and appetite effects, and cardiovascular effects. Convulsions were observed in nonclinical studies at therapeutically-relevant viloxazine doses. However, the review team found no evidence that viloxazine is associated with in humans. The nonclinical signal will be described in labeling. There were higher rates of suicidal ideation with viloxazine ER compared to placebo, but the overall rates were low. This risk can be mitigated by labeling (patients on viloxazine should be monitored for the emergence of SI/B). Viloxazine ER was associated with decreased appetite, decreased age-appropriate weight gain, increased heart rate, and increased diastolic blood pressure. However, those risks appear no worse than for most approved ADHD treatments (i.e., and ), and can be managed by appropriate labeling (patients should have their weight and vital signs monitored before and during viloxazine ER treatment).

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There are no approvability issues with the drug substance, drug product, environmental impact, labeling, or biopharmaceutics information. The manufacturing facility was previously inspected, but not since relocating in February 2020. Because FDA inspectors could not travel for inspection (based on the Agency’s global travel warning)—and the facility could not provide documentation of procedures for handling laboratory records or appropriate re-qualification of analytical instruments—the NDA will receive a Complete Response. Postmarketing requirements (PMRs) will include a single-arm pregnancy study, a milk-only lactation study, and a hepatic impairment study. PMRs will also include the studies from the Applicant’s agreed iPSP: a safety and efficacy study, and a long-term safety study of viloxazine ER in patients with ADHD ages 4 to less than 6 years old. In summary, the Applicant has provided substantial evidence of effectiveness of viloxazine ER, and the risks of viloxazine ER are acceptable for the proposed indication. However, a Complete Response Letter will be issued because of the manufacturing deficiency described above.

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2. Benefit-Risk Assessment

Table 2. Benefit-Risk Framework Dimension Evidence and Uncertainties Conclusions and Reasons

Analysis of  Attention deficit hyperactivity disorder (ADHD) is a  Effective treatment of ADHD reduces functional impairment Condition childhood-onset neurodevelopmental disorder that is in the short-term, and may result in long-term benefits, such characterized by hyperactivity, impulsivity, or inattention as a reduced risk of substance abuse and reduced risk of severe enough to cause functional impairment. injuries.  ADHD is the most common neurodevelopmental disorder of childhood.  ADHD has been associated with , suicidal behavior, substance abuse, and poor educational and occupational outcomes.

Current  medications are the first-line pharmacologic  Stimulant and nonstimulant treatment options are available Treatment treatment for ADHD. for ADHD. Nonstimulant medications are frequently used Options when patients are unable to tolerate adverse reactions  Stimulant medications carry potential risks of blood associated with stimulants or when patients prefer a pressure and heart rate increases, psychiatric adverse nonstimulant treatment. Viloxazine ER would provide reactions including psychosis and mania, growth patients and healthcare professionals with an additional suppression, lowered seizure threshold, , nonstimulant treatment option. decreased appetite and weight, abuse, misuse, and diversion.  Available nonstimulant options for treatment of ADHD include atomoxetine and alpha ( extended-release and extended-release). None of these nonstimulant medications is controlled under the Controlled Substances Act.

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Dimension Evidence and Uncertainties Conclusions and Reasons  Atomoxetine is associated with risks of , decreased appetite, suicidal ideation, severe liver injury, serious cardiovascular events, increased heart rate and blood pressure, emergence of psychosis or mania, aggression, and growth effects.  Guanfacine extended-release and clonidine extended- release are associated with somnolence/sedation, bradycardia, syncope, cardiac conduction abnormalities, and rebound hypertension.

Benefit  The Applicant conducted four adequate and well-controlled  Viloxazine ER demonstrated statistically significant efficacy studies to assess the efficacy of viloxazine ER for the compared to placebo for the 100 mg, 200 mg, and 400 mg treatment of ADHD in patients ages 6 to 17 years. daily dosages in patients ages 6 to 11 years and for the  The primary efficacy endpoint in all four studies was the 200 mg and 400 mg daily dosages in patients ages 12 to change from baseline in the ADHD Rating Scale–5 (ADHD- 17 years. The clinical meaningfulness of the results is RS-5), an 18-question scale that measures the core supported by the positive findings on the CGI-I across dose symptoms of ADHD. A reduction in the ADHD-RS-5 total groups. score indicates an improvement in ADHD symptoms.  There was no evidence that the 600 mg dosage of  The Clinical Global Impression-Improvement (CGI-I) scale viloxazine provides benefit additional to that of lower was included as a key secondary endpoint in the studies. dosages. The CGI-I assesses whether a patient’s illness has  There is substantial evidence of effectiveness to support improved or worsened over time. Responses on the CGI-I approval of viloxazine ER (100 mg, 200 mg, 400 mg) for are rated on a 7-point Likert scale. the treatment of ADHD in pediatric patients ages 6 to 17  Study 812P301 evaluated the efficacy of viloxazine ER years. 100 mg and 200 mg daily in patients ages 6 to 11 years. Viloxazine ER was well-tolerated in the patient population, Both dosages were statistically significantly superior to and may have safety advantages when compared with placebo in the mean change from baseline in ADHD-RS-5 stimulant medications (i.e., lack of human abuse liabilty total score at the end of study, with a least square (LS) and rare occurrence of psychosis). mean treatment difference to placebo of -5.8 for the 100 mg dose and -6.9 for the 200 mg dose.  Study 812P303 evaluated the efficacy of the 200 mg and 400 mg daily dosages in patients ages 6 to 11 years, and similarly demonstrated a statistically significant effect on the primary endpoint for both dosages. The LS mean difference to placebo was -6.0 for the 200 mg dose and -5.8 for the 400 mg dose.

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Dimension Evidence and Uncertainties Conclusions and Reasons

 In both studies that evaluated viloxazine ER in the patients 6 to 11 years of age (812P301 and 812P303), a statistically significant improvement in the CGI-I was observed.  Study 812P302 evaluated the efficacy of the 200 mg and 400 mg doses in patients ages 12 to 17 years. The LS mean difference to placebo in ADHD-RS-5 was -4.5 for viloxazine ER 200 mg and -5.1 for viloxazine ER 400 mg. A statistically significant improvement was also observed in the CGI-I for both dosages, compared to placebo.  Study 812P304, which evaluated the efficacy of the 400 mg and 600 mg daily dosages of viloxazine ER in patients ages 12 to 17 years, did not demonstrate a statistically significant difference between viloxazine ER and placebo on the primary endpoint. This finding could be attributable to type II error, a robust placebo response in this study, or a lack of treatment effect.  In the controlled studies, a small proportion of patients (3.5%) discontinued with viloxazine ER because of adverse events, and few patients reported serious adverse events. Unlike stimulant medications, viloxazine ER was not associated with significant abuse liability or emergence of psychotic symptoms.

Risk and  The most common treatment-emergent adverse events  The submitted data were sufficient to assess the safety of Risk associated with viloxazine ER in pediatric patients with viloxazine ER in pediatric patients ages 6 to 17 years with Management ADHD (and occuring more frequently than in placebo- ADHD. None of the identified safety issues would preclude treated patients) were somnolence/sedation (16.1%), approval of viloxazine ER. The risks can be described headache (6.9%), decreased appetite (7.4%), fatigue adequately in labeling to allow for safe use of the drug. (6.4%), (5.4%), (4.6%), vomiting  The most common treatment-emergent adverse event was (4.2%), and irritability (3.3%). somnolence/sedation. Labeling will include a warning that  Viloxazine ER was associated with higher rates of suicidal alerts healthcare professionals to the potential risk to ideation and behavior, increases in heart rate and diastolic patients when operating machinery or driving. blood pressure, and decreased weight gain.  A boxed warning indicating the risk of suicidal ideation and  In animal studies, maternal deaths occurred in late behavior will inform healthcare professionals of this serious pregnancy in rats and mice that were exposed to viloxazine. 18 Integrated Review Template, version date 2019/10/16 Reference ID: 4698714

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Dimension Evidence and Uncertainties Conclusions and Reasons Immediate-release viloxazine was previously authorized in and possibly unexpected risk. Europe for the treatment of depression. Limited data about  Labeling will advise healthcare professionals to monitor the safety of viloxazine in pregnancy are available in the heart rate, blood pressure, and weight. literature or postmarketing databases.  Use of viloxazine ER is not recommended in pregnancy.  Viloxazine ER increases the concentration of CYP1A2 The Applicant should conduct a postmarketing single-arm substrates five-fold. pregnancy study as well as a milk-only lactation study to  Seizures occurred in multiple animal species. No seizures evaluate the potential risks to pregnant and lactating occurred in the controlled clinical trials. Seizures were patients. reported in an uncontrolled study of viloxazine ER and in  Viloxaxine will be contraindicated in patients receivig postmarketing reports for immediate-release viloxazine, but concomitant administration of sensitive CYP1A2 substrates the association between these events and viloxazine ER or CYP1A2 substrates with a narrow therapeutic range. exposure is unclear.  Labeling will also detail the nonclinical findings of  Postmarketing databases include reports of liver injury convulsions. associated with immediate-release viloxazine. Transaminase values were more likely to shift from within  Routine postmarketing surveillance will provide further the reference range to above the reference range in information about any potential risk of seizure or liver injury patients receiving viloxazine ER in placebo-controlled with viloxazine exposure. studies; however, transaminase elevations were modest, and no cases of drug-induced liver injury were identified.

Conclusions Regarding Benefit-Risk ADHD is a common and impairing neurodevelopmental disorder of childhood. Viloxazine ER would provide another treatment option for patients who are unable to tolerate stimulant medications, patients for whom the risks of stimulants may outweigh the benefits, and patients who simply prefer a nonstimulant treatment. The applicant provided substantial evidence that viloxazine ER is effective for the treatment of ADHD in pediatric patients ages 6 to 17 years, at daily dosages between 100 and 400 mg in patients 6 to 11 years of age, and daily dosages between 200 and 400 mg in patients 12 to 17 years of age. Overall, the safety profile of viloxazine ER is acceptable for the intended population, and the identified risks can be appropriately mitigated with strategies outlined in labeling. Viloxazine ER has some safety advantages when compared to stimulant medications— namely, low human abuse liability and no clear association with psychosis events. However, patients who received viloxazine ER did experience psychiatric adverse events (particularly irritability, insomnia, and suicidal ideation and behavior) at greater rates than those on placebo. Although no manic episodes have been reported in the development program, the safety of viloxazine ER exposure in patients with a bipolar diathesis is unknown. Viloxazine ER was associated with increased heart rate and diastolic blood pressure and decreased appetite and weight gain, as are stimulants and atomoxetine. Viloxazine ER, like the currently approved nonstimulant 19 Integrated Review Template, version date 2019/10/16 Reference ID: 4698714

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treatments for ADHD, was also associated with somnolence/sedation. Viloxazine ER does not appear to provide notable advantages over other nonstimulant ADHD medications, but is another safe and effective treatment option. As described in the proposed prescribing information, patients receiving viloxazine ER should be screened for risk of bipolar disorder and monitored for the emergence of suicidal ideation and behavior. Healthcare professionals should also measure weight and vital signs before and during viloxazine ER treatment. The review team recommends approval of viloxazine ER for the proposed indication.

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II. Interdisciplinary Assessment

3. Introduction

Supernus Pharmaceuticals, Inc. (the Applicant) has submitted a 505(b)(1) new drug application (NDA) for viloxazine extended-release capsules for the treatment of attention deficit hyperactivity disorder (ADHD) in pediatric patients ages 6 to 17 years. ADHD is a childhood-onset neurodevelopmental disorder characterized by a persistent pattern of inattention, hyperactivity-impulsivity, or a combination thereof that interferes with functioning or development. Symptoms must persist for at least 6 months and at least some symptoms must have been present prior to the age of 12 years (American Psychiatric Association 2013) to meet diagnostic criteria. According to data from the National Center for Health Statistics (NCHS), the prevalence of diagnosed ADHD in U.S. children and adolescents ages 3 to 17 years has increased over the last decade. The prevalence of ADHD in this population was 8.5% in the years 2009 to 2011, and 9.5% in the years 2015 to 2017 (Zablotsky et al. 2019). ADHD may persist into adulthood. The prevalence of ADHD among U.S. adults has also increased from 3.4% in 2007 to 4.3% in 2012 (London and Landes 2019). ADHD has been associated with depression, suicidal behavior, substance abuse, and poor educational and occupational outcomes (Chan et al. 2016). Stimulant medications are the first-line pharmacologic treatments for ADHD. Stimulant medications carry potential risks of blood pressure and heart rate increases, psychiatric adverse reactions, growth suppression, lowered seizure threshold, insomnia, and decreased appetite and weight. Stimulants are Schedule II/IIN controlled substances with significant human abuse liability potential; abuse, misuse, and diversion can occur. Patients who are unable to tolerate adverse effects of stimulant medications, particularly appetite suppression, insomnia, and psychiatric adverse reactions, may benefit from nonstimulant treatment options. Nonstimulant medications may also be considered in clinical scenarios in which there are concerns about potential abuse or diversion of stimulants or when patients express a preference for nonstimulants. Three nonstimulant medications—atomoxetine, guanfacine extended-release, and clonidine extended-release—have been approved for the treatment of ADHD to date. Atomoxetine is a norepinephrine reuptake inhibitor that is indicated for use in children, adolescents, and adults. Atomoxetine labeling includes a boxed warning regarding the potential risk of suicidal ideation. Other warnings and precautions outlined in its labeling include severe liver injury, serious cardiovascular events, anaphylaxis, urinary hesitancy and retention, priapism, increased heart rate and blood pressure, emergent psychotic or manic symptoms, aggressive behavior and hostility, and growth effects. Guanfacine extended-release and clonidine extended-release are centrally acting α2 adrenergic antagonists that are indicated for the treatment of ADHD as monotherapy or as adjunctive therapy to stimulant medications. Warnings and precautions for guanfacine extended- release and clonidine extended-release include: , bradycardia, syncope, sedation/somnolence, cardiac conduction abnormalities, and rebound hypertension.

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All three approved nonstimulant treatments for ADHD are unscheduled. Buproprion, immediate-release guanfacine and clonidine, , , and have been used as off-label pharmacological treatments for ADHD. Pediatric data on the use of these medications for ADHD are limited. Patients with ADHD may also benefit from non-pharmacologic interventions such as behavioral therapy, parent guidance, and educational modifications. However, data suggest that pharmacological treatment results in greater short-term symptomatic improvement than intensive behavioral therapy (Molina et al. 2009). Pharmacological treatment of ADHD may also result in a lower risk of substance-use disorder and injuries; however, data on the long-term benefits and risks of pharmacological treatment for ADHD are limited and frequently confounded (Chang et al. 2019). In the NDA submission, the Applicant describes viloxazine extended-release as a norepinephrine reuptake inhibitor, 5HT2B serotonin , and 5HT2C serotonin receptor . The Applicant reports that viloxazine extended-release also potentiates serotonergic activity by mechanisms other than serotonin reuptake. The Applicant emphasizes the role of the noradrenergic and serotonergic systems in regulating executive functioning, attention, and behavior, and posits that the effects of viloxazine extended-release on these systems will lead to improvement in ADHD symptoms. Based on published nonclinical studies that did not find evidence of reinforcing effects, withdrawal, or other signs typically associated with abuse, the Applicant has concluded that viloxazine extended-release has low potential for abuse in humans. The immediate-release formulation of viloxazine was initially marketed in Europe as an antidepressant in the late 1970s, and subsequently withdrawn in 2008 for commercial reasons. Although viloxazine was previously marketed in Europe, it has never been approved or marketed in the United States for any indication. Prior to NDA submission, the Agency interacted with the Applicant in two pre-IND meetings (March 2010 and June 2013), an End-of-Phase 2 meeting (July 2017), a CMC End-of-Phase 2 meeting (July 2017), a pre-NDA meeting (July 2019), as well as via advice letters and other communications. The Applicant and the Agency came to agreement on the use of the ADHD Rating Scale–5 (ADHD-RS-5) as the primary efficacy endpoint in the phase 3 safety and efficacy studies. The Agency expressed reservations about the Applicant’s planned use of the Clinical Global Impressions-Improvement (CGI-I) scale as a secondary endpoint because of the susceptibility of this scale to recall bias. The Agency expressed concern about the lack of a safety margin between the no observed adverse effect level (NOAEL) exposures for seizures in animals and the blood levels already attained in clinical trials. After review of published data submitted by the Applicant, the Agency agreed that there did not appear to be a clear seizure risk associated with viloxazine in humans. Please see the detailed Summary of Regulatory History in Appendix III.12. 3.1. Review Issue List

 Review issue 1 — (b) (4)  Review issue 2

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— Inclusion of CGI-I results in labeling  Review issue 3 — Clinical significance of seizures and convulsions in nonclinical studies  Review issue 4 — Risk of suicidal ideation and behavior  Review issue 5 — Risk of somnolence/sedation  Review issue 6 — Clinical significance of weight/appetite effects  Review issue 7 — Clinical significance of heart rate and blood pressure effects  Review issue 8 — Clinical significance of postmarketing reports of liver injury with immediate-release viloxazine  Review issue 9 — Applicant’s (b) (4) proposal  Review issue 10 — Differences in animal and human  Review issue 11 — Concomitant administration of viloxazine with CYP1A2 substrates (e.g., )  Review issue 12 — Dosing of viloxazine in renal-impaired patients 3.2. Approach to the Review The Applicant submitted four phase 3, double-blind, placebo-controlled studies (812P301, 812P302, 812P303, and 812P304) as evidence of efficacy and safety. Table 3 provides an overview of the patient populations, trial designs, endpoints, and enrollment for these studies. In addition, a phase 2 dose-ranging study (812P202) was considered as supportive evidence of efficacy and safety. Long-term safety data from an ongoing open-label extension study (812P310), including updated data on adverse events, vital signs, and laboratory assessments provided in the 120-day safety update, were also considered in the safety review.

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Table 3. Clinical Trials Submitted in Support of Efficacy and Safety Determinations1 for Viloxazine Extended-Release Number of Trial Drug, Dose, Number Primary and Key Subjects Number of Identifier Trial Population Trial Design Treated, Duration Secondary Endpoints Randomized Trial Sites 812P301 Subjects 6 to 11 Control type: Placebo Drug: Viloxazine Primary: Planned: 432 Centers: 34 years of age with concurrent CFB in the ADHD-RS-5 ADHD Dose: 100 mg QD; 200 mg Total Score at EOS Actual: 477 Countries: 1 Randomization: Standard QD; placebo randomization Secondary: Number treated: 154; CGI-I score at EOS; Blinding: Double-blind 161; 159 CFB in the Conners 3-Parent Composite Biomarkers: No biomarkers Duration: approximately T-Score at EOS; CFB in 10 weeks the WFIRS-P Total Innovative design features: Average Score at EOS None 812P302 Subjects 12 to Control type: Placebo Drug: Viloxazine Primary: Planned: 300 Centers: 33 17 years of age concurrent CFB in the ADHD-RS-5 with ADHD Dose: 200 mg QD; 400 mg Total Score at end of Actual: 310 Countries: 1 Randomization: Standard QD; placebo study (EOS) randomization Number treated: 99; 105; Secondary: Blinding: Double-blind 104 CGI-I score at EOS; CFB in the Conners Biomarkers: No biomarkers Duration: approximately 3-Parent Composite 10 weeks T-Score at EOS; CFB in Innovative design features: the WFIRS-P Total None Average Score at EOS 812P303 Subjects 6 to 11 Control type: Placebo Drug: Viloxazine Primary: Planned: 300 Centers: 28 years of age with concurrent CFB in the ADHD-RS-5 ADHD Dose: 200 mg QD; 400 mg Total Score at EOS Actual: 313 Countries: 1 Randomization: Standard QD; placebo randomization Secondary: Number treated: 107; 100; CGI-I score at EOS; Blinding: Double-blind 103 CFB in the Conners 3-Parent Composite Biomarkers: No biomarkers Duration: approximately 12 T-Score at EOS; CFB in weeks the WFIRS-P Total Innovative design features: Average Score at EOS None 24 Integrated Review Template, version date 2019/10/16 Reference ID: 4698714

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Number of Trial Drug, Dose, Number Primary and Key Subjects Number of Identifier Trial Population Trial Design Treated, Duration Secondary Endpoints Randomized Trial Sites 812P304 Subjects 12 to Control type: Placebo Drug: Viloxazine Primary: Planned: 300 Centers: 29 17 years of age concurrent CFB in the ADHD-RS-5 with ADHD Dose: Total Score at EOS Actual: 297 Countries: 1 Randomization: Standard 400 mg QD; 600 mg QD; randomization placebo Secondary: CGI-I score at EOS; Blinding: Double-blind Number treated: 100; 99; CFB in the Conners 97 3-Parent Composite Biomarkers: No biomarkers T-Score at EOS; CFB in Duration: approximately the WFIRS-P Total Innovative design features: 11 weeks Average Score at EOS None Source: CSR and adsl.xpt; Table created by the Clinical Data Scientist. 1 Includes all phase 3 clinical trials. Abbreviations: ADHD = attention-deficit/hyperactivity disorder; CFB = change from baseline; CGI-I = Clinical Global Impression–Improvement scale; DB = double-blind; EOS = end of study; N=number of subjects; QD = once daily; RS = rating scale; WFIRS-P = Weiss Functional Impairment Rating Scale-Parent Report

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4. Patient Experience Data

Table 4. Patient Experience Data Submitted or Considered Data Submitted in the Application Check if Section Where Discussed, Submitted Type of Data if Applicable Clinical outcome assessment data submitted in the application ☒ Patient-reported outcome Section Error! Reference source not found. Section II.6.4 ☒ Observer-reported outcome ☒ Clinician-reported outcome ☐ Performance outcome Other patient experience data submitted in the application ☐ Patient-focused drug development meeting summary ☐ Qualitative studies (e.g., individual patient/caregiver interviews, focus group interviews, expert interviews, Delphi Panel) ☐ Observational survey studies ☐ Natural history studies ☐ Patient preference studies ☐ Other: (please specify) ☐ If no patient experience data were submitted by Applicant, indicate here. Data Considered in the Assessment (but Not Submitted by Applicant) Check if Section Where Discussed, Considered Type of Data if Applicable ☐ Perspectives shared at patient stakeholder meeting ☐ Patient-focused drug development meeting summary report ☐ Other stakeholder meeting summary report ☐ Observational survey studies ☐ Other: (please specify)

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5. Pharmacologic Activity, Pharmacokinetics, and Clinical Pharmacology

Pharmacologic properties of viloxazine that are relevant to the interpretation of benefit and risk are summarized in Table 5. This includes information related to the viloxazine extended-release formulation. The major metabolite, 5-hydroxyviloxazine-gluconate, is not pharmacologically active; therefore, information related to it is not included in Table 5. Table 5. Summary of General Clinical Pharmacology and Pharmacokinetics Characteristic Drug Information Pharmacologic Activity Mechanism of action Norepinephrine reuptake inhibitor. Active moieties Viloxazine, the parent compound. QT prolongation At a dose three-fold the maximum recommended dose, viloxazine does not prolong the QT interval to any clinically relevant extent. There was no effect of viloxazine on the PR interval or QRS duration in healthy volunteers. However, nonclinical studies suggest a potential for viloxazine to inhibit cardiac sodium channels. General Information Bioanalysis A validated liquid chromatography with tandem mass spectrometry (LC/MS/MS) method was used to determine the concentrations of viloxazine and 5-hydroxyviloxazine glucuronide in plasma and . The accuracy, precision, sensitivity, stability, incurred sample reanalysis and reproducibility met the acceptance criteria. The analytical method and its validation are acceptable. Healthy subjects versus patients The PK for ADHD patients and healthy subjects is expected to be similar based on the population pharmacokinetic analysis. Drug exposure at steady state following the Parameter Mean ± SD* therapeutic dosing regimen (or a single AUCtau 24.7±8.52 µg*h/mL dose, if more relevant for the drug) Cmax,ss 1.66±0.50 µg/mL Cmin 0.39±0.23 µg/mL %FL 128±27.8% Median Tmax (range) 5 (2, 9) hours *Viloxazine PK values at steady state after multiple doses of viloxazine ER 200 mg once daily. Source: Applicant’s Study 812P103 page 46 Range of effective dose(s) or exposure 100 to 400 mg Maximally tolerated dose or exposure 600 mg Dose proportionality 100 to 600 mg dose range Accumulation No significant accumulation from single dose to steady state Time to achieve steady state After 2 days of once-daily dosing Bridge between to-be-marketed and To-be-marketed formulation was used in the pivotal formulations phase 3 and key pharmacokinetic studies

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Characteristic Drug Information Absorption Bioavailability Relative bioavailability with immediate release (IR) oral capsule as reference was about 87% Median Tmax (range) Sprinkled, fed, and fasted 5 (3, 7), 7 (4,18), and 5 (4, 9) hours, respectively Food effect (fed/fasted) Viloxazine (See Appendix III.14.3.1) Geometric least square mean ratio and AUC0-∞ 92.35% (86.96, 98.07) 90% CI Cmax 90.86% (84.05, 98.21) Tmax 7 vs. 5 hours for fed and fasted, respectively Food effect (sprinkled on applesauce/intact) fasted. Geometric least AUC0-∞ 95.37% (89.80, 101.28) square mean ratio and 90% CI Cmax 90.10% (83.35, 97.40)

Fed state: Within 30 minutes after start of high-fat, high- calorie standard meal (800-1000 kcal) after an overnight fast of 10 hours Distribution Volume of distribution 14.6 L (Based on the population pharmacokinetic analysis) Plasma protein binding 76-82% bound to human plasma proteins over concentration range of 0.5 to 10 µg/mL Drug as substrate of transporters Not a substrate of transporters (Pgp, BCRP, OATiB1/3, OAT, OCT, MATE) Elimination Mass balance results Following administration of a single oral dose of [14C]- viloxazine, a mean of about 103% of the radioactivity administered was recovered, with approximately 90% of the dose recovered within the first 24 hours of dosing. An average of 102% of the total radioactivity was recovered from the urine and 0.67% from the . Urinary excretion is the major route of elimination of viloxazine and its metabolites. Unchanged viloxazine and the 5-hydroxy glucuronide metabolite were the only moieties excreted in urine in amounts greater than 10% of total radioactivity. Unchanged viloxazine and 5-hydroxyviloxazine-glucuronide accounted for about 53.1% and 10.6% of total radioactivity in plasma, respectively. Clearance 0.865 L/hour (based on the population pharmacokinetic analysis) Half-life 7.02±4.74 hours Metabolic pathway(s) 1) by CYP2D6, then glucuronidation to 5-OH-viloxazine glucuronide; 2) N-carboxylation, then glucuronidation to a minor metabolite Primary excretion pathways (% dose) Renal. Less than 1% excreted via feces Intrinsic Factors and Specific Populations Body weight The population pharmacokinetic analysis indicated that exposure (Cmax and AUC) increases with decreasing weight. Exposures in children 6 to 11 years are 40-50% higher than in adolescents ages 12 to 17 years at the same dose. Age The population pharmacokinetic analysis indicated that pharmacokinetics of viloxazine is not affected by age Renal impairment AUC is about 90% higher in severely renal-impaired patients. A maximum dose of 200 mg is recommended in patients with severe renal impairment. 28 Integrated Review Template, version date 2019/10/16

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at the target daily dose of 300 mg) showed a gradually widening difference between the viloxazine and placebo groups. Eight (30.8%) subjects in the viloxazine group and 1 (4.0%) subject in the placebo group reduced the dosage to 150 mg/day due to adverse events (AEs). The most common AEs in viloxazine-treated patients were nausea (38.5%), decreased appetite (30.8%), headache (30.8%), insomnia (30.8%), and dry mouth (23.1%). Study 812P202 was a randomized, double-blind, placebo-controlled, multicenter, 5-arm, parallel- group, dose-ranging study to evaluate the efficacy, safety, and tolerability of viloxazine ER as monotherapy for ADHD in children. The study enrolled 200 subjects aged 6 to 12 years, who were randomized at a 1:2:2:2:2 ratio to placebo or active treatment (viloxazine ER 100, 200, 300, or 400 mg). When compared to placebo, doses of 200 to 400 mg showed a statistically significant effect on ADHD Rating Scale IV (ADHD-RS-IV) total score. A reduction of about 8 units from baseline in the ADHD-RS-IV total score was observed for doses of 200 to 400 mg. However, the 100 mg dose showed a reduction of 6.2 units from baseline in the ADHD-RS-IV total score, which was not statistically significant when compared to placebo. Based on the findings discussed above and considering the differences in body weight across age groups (6 to 11 and 12 to 17 years), the Applicant selected a dosage range of 100 to 600 mg viloxazine ER capsules to evaluate in the phase 3 studies. 6.2. Clinical Trials Intended to Demonstrate Efficacy 6.2.1. Trial Design The Applicant conducted four phase 3, multicenter, randomized, double-blind, three-arm, placebo-controlled studies to evaluate the safety and efficacy of viloxazine ER in the pediatric population—Studies 812P301, 812P302, 812P303, 812P304. Studies 812P301 and 812P303 evaluated viloxazine ER in children ages 6 to 11 years. Studies 812P302 and 812P304 evaluated viloxazine ER in adolescents ages 13 to 17 years. Doses ranged from 100 mg to 400 mg once daily in patients ages 6 to 11 years, and from 200 mg to 600 mg once daily in patients ages 12 to 17 years. Each study included a screening phase, a dose-titration phase, and a 5-week, fixed-dose, maintenance phase. All four studies were conducted entirely in the United States. Figure 1 depicts the design of Study 812P301. The designs of the other phase 3 studies mirrored that of Study 812P301, except for differences in age, dose range, and duration of the titration period. See Appendix III.15 for a more complete description of the phase 3 studies.

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considered medically healthy by the investigator (as assessed by physical examination, medical history, clinical laboratory tests, vital signs, and ECG). Female patients of childbearing potential had to either practice abstinence or agree to use effective methods of birth control throughout the study. The exclusion criteria included the presence of major psychiatric, neurological, or other physical health conditions. Patients with a personal history or family history of seizure disorders were specifically excluded. The inclusion and exclusion criteria were appropriate to select a representative patient population and to mitigate potential risks to patients in the studies. ADHD diagnosis in clinical practice is based on application of the DSM-5 criteria, which were also used in the phase 3 studies. Participants had prominent ADHD symptoms at baseline based on ADHD-RS-5 scores. The study excluded patients with a known history of seizure disorder or high risk for seizures given that the risk of seizures in humans was unknown (convulsions occurred in multiple species in nonclinical studies). The protocols required reporting of seizures and seizure-like events as adverse events of special interest. The protocols also included appropriate prospective monitoring for potential safety signals of interest in this population, including cardiovascular adverse events, negative impacts on growth, and suicidal ideation. The inclusion and exclusion criteria for Study 812P202 were similar to those for the phase 3 studies. Patients from Studies 812P202, 812P301, 812P302, 812P303, and 812P304 were eligible to enroll in Study812P310, the long-term safety extension. 6.2.3. Statistical Analysis Plan In each study, important design features, such as endpoints, primary analysis methods, multiplicity adjustment method, and sample size were prespecified in the statistical analysis plan. The primary efficacy outcome was the change from baseline to EOS in ADHD-RS-5 total score, which was the measure used in all of the other studies. The primary endpoint was targeted on the highest dose first, followed by lower doses, in sequence (e.g., 200 mg/day, 100 mg/day in Study 301). A similar hierarchy was used for the secondary endpoints. The proposed key secondary efficacy endpoints were:  CGI-I score at EOS.  Change from baseline in the Conners 3-Parent Composite T-Score at EOS.  Change from baseline in the WFIRS-P total average score at EOS. Multiplicity adjustment: To account for potential type I error inflation caused by comparisons of multiple dose-groups to placebo, a sequential testing procedure was used to assess the primary (high, low doses) and secondary endpoints (high, low doses) in all four trials. Protocol amendments: (i) Study 301; the original protocol, which was issued on 11 July 2017, was amended three times: 14 August 2017, 7 September 2017, and 17 September 2017. (ii) Study 302; the original protocol, which was issued on 11 July 2017, was amended three times: 14 August 2017, 7 September 2017, and 18 September 2018. (iii) Study 303; the original protocol, which was issued on 11 July 2017, was amended three times: 14 August 2017, 7 September 2017, and 22 August 2018. (iv) Study 304; the original protocol, which was issued on 11 July 2017, was amended three times: 14 August 2017, 7 September 2017, and 12 October 2018. Analysis method: The prespecified primary efficacy analysis model, mixed model repeated

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measures (MMRM), was used to evaluate the treatment effect in the studies. The model, which assesses the change from baseline in ADHD-RS-5, comprises the baseline ADHD-RS-5 total score, age group category, treatment, visit (in weeks), and treatment-by-visit interaction as fixed independent variables. MMRM assumes a missing at random missing data mechanism. The model parameters were to be estimated using the restricted maximum-likelihood method, with unstructured variance-covariance matrix and Kenward-Roger approximation to estimate denominator degrees of freedom. Sample size and power: The sample size calculation was based on a two-sample t-test and treatment effect assumptions from previously completed phase 2b trials. Below are the sample size and power calculation, which are extracted from the Applicant’s statistical analysis plan. Study 301: One hundred and four subjects per treatment group in the intent-to-treat (ITT) population will yield 90% power at a significance level of 0.05 (two-sided) using a two-sample t- test with equal allocation to the treatment groups. This assumes an effect size of 0.453, observed in the comparison of SPN-812 100 mg and placebo in the SPN-812 phase 2b study (based on the CFB to endpoint in the ADHD-RS-IV total score). A total of 432 subjects (144 subjects in each of the three treatment groups) will be randomized to account for an anticipated 27.9% of randomized subjects not completing the study. Study 302 and Study 303: Seventy-two subjects per treatment group in the ITT population will yield 90% power at a significance level of 0.05 (two-sided) using a two-sample t-test with equal allocation to the treatment groups. This assumes an effect size of 0.547, as observed in the comparison of SPN-812 200 mg and placebo in the SPN-812 phase 2b study (based on the CFB to endpoint in the ADHD-RS-IV total score). A total of 300 subjects (100 subjects in each of the three treatment groups) will be randomized to account for an anticipated 27.9% of randomized subjects not completing the study. Study 304: Seventy-two subjects per treatment group in the ITT population will yield 90% power at a significance level of 0.05 (two-sided) using a two-sample t-test with equal allocation to the treatment groups. This assumes an effect size of 0.547, which was observed in the comparison of SPN-812 200 mg and placebo in the SPN 812 phase 2b study (based on the CFB to endpoint in the ADHD-RS-IV total score) and will maintain consistency in the sample size assumption used between this clinical trial and the SPN-812 P302 study in the adolescent population. A total of 300 subjects (100 subjects in each of the three treatment groups) will be randomized to account for an anticipated 27.9% of randomized subjects not completing the study. 6.2.4. Results of Analyses of Clinical Trials/Studies Intended to Demonstrate Efficacy This section summarizes the baseline demographics and disease characteristics, patient dispositions, and primary efficacy results to support the use of viloxazine ER in the treatment of pediatric ADHD. Overall, the baseline demographics and disease characteristics were well-balanced in patients receiving viloxazine ER and patients receiving placebo. The studies were conducted entirely in the United States. Greater than 60% of the patients were male, which is consistent with the gender ratios observed in clinical practice (Ramtekkar et al. 2010). The study population was

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ethnically diverse, although patients of Asian, Alaskan Native, Pacific Islander, and Native Hawaiian heritage were underrepresented. Black and Latino children and adolescents were over-represented in the sample; although a body of literature suggests that minority children are less likely to receive an ADHD diagnosis, more recent data indicate that Black children may be diagnosed with ADHD more frequently than those of other ethnicities (Morgan et al. 2013; Zablotsky and Alford 2020). Although the study population may differ somewhat from the general clinical population, the treatment groups had similar racial and ethnic compositions, making it unlikely that sociodemographic factors influenced the study results. Table 6 summarizes the baseline demographic characteristics of the phase 3 controlled studies. Table 6. Baseline Demographic Characteristics, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) Ages 6 to 11 Years Ages 12 to 17 Years Total Treatment Placebo Treatment Placebo Treatment Placebo Characteristic N=522 N=262 N=403 N=201 N=925 N=463 Sex, n (%) Male 335 (64) 166 (63) 276 (69) 119 (59) 611 (66) 285 (62) Female 187 (36) 96 (37) 127 (32) 82 (41) 314 (34) 178 (38) Age, years, n (%) Mean (SD) 8.5 (2) 8.5 (2) 13.9 (2) 13.8 (2) 10.9 (3) 10.8 (3) Median 8.0 8.0 14.0 14.0 11.0 11.0 (min, max) (6.0, 11.0) (6.0, 11.0) (12.0, 17.0) (12.0, 17.0) (6.0, 17.0) (6.0, 17.0) Age group, years,

n (%) 6–9 356 (68) 175 (67) 0 0 356 (39) 175 (38) 10–11 166 (32) 87 (33) 0 0 166 (18) 87 (19) 12–14 0 0 267 (66) 134 (67) 267 (29) 134 (29) 15–17 0 0 136 (34) 67 (33) 136 (15) 67 (15) Race, n (%) American Indian 2 (0.4) 3 (1) 4 (1) 1 (1) 6 (1) 4 (1) or Alaska Native Black or African 226 (43) 111 (42) 142 (35) 64 (32) 368 (40) 175 (38) American Multiple 22 (4) 11 (4) 11 (3) 8 (4) 33 (4) 19 (4) White 272 (52) 135 (52) 243 (60) 128 (64) 515 (56) 263 (57) Asian 0 2 (1) 2 (1) 02 (0.2) 2 (0.4) Native Hawaiian or other Pacific 0 0 1 (0.2) 0 1 (0.1) 0 Islander Ethnicity, n (%) Hispanic or 152 (29) 68 (26) 125 (31) 63 (31) 277 (30) 131 (28) Latino Not Hispanic or 369 (71) 194 (74) 278 (69) 137 (68) 647 (70) 331 (72) Latino Missing 1 (0.2) 0 0 1 (1) 1 (0.1) 1 (0.1) Country of

participation, n (%) United States 522 (100) 262 (100) 403 (100) 201 (100) 925 (100) 463 (100) Source: adsl.xpt; Software, Python. Created by the Clinical Data Scientist and Clinical Review Team. Abbreviations: Max = maximum; min = minimum; N=number of subjects in treatment group; N=number of subjects with a given characteristic; SD = standard deviation The mean baseline weight in patients ages 6 to 11 years was 32 kg in the viloxazine ER treatment groups and 30.9 in the placebo groups. The mean baseline weight in patients ages 12 to

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17 years was 57.9 kg in the viloxazine ER treatment groups and 55.9 kg in the placebo groups. Similar proportions of patients in the viloxazine ER and placebo groups were taking psychostimulants or other agents used for ADHD (i.e., alpha agonists or atomoxetine) at screening (28.3% and 28.8% of patients respectively). The baseline ADHD-RS-5 score in viloxazine ER–treated patients was 42.5 (SD 7.4), compared to 41.8 (SD 7.4) in placebo-treated patients. Table 7 and Table 8 summarize the patient disposition and reasons for study discontinuation in the phase 3 controlled studies. Patients who received viloxazine ER were more likely than patients receiving placebo to discontinue the studies because of adverse events. However, only approximately 3.5% of viloxazine ER–treated patients dropped out because of adverse events. Table 7. Patient Screening and Randomization (Studies 812P301, 812P302, 812P303, and 812P304) Screening Disposition Study 812P301 Study 812P302 Study 812P303 Study 812P304 Patients screened 587 379 393 417 Patients not randomized 110 69 80 120 Screening failures 110 69 80 120 Patients randomized 477 310 313 297 Source: adds.xpt; Software, R. Table created by the Clinical Data Scientist. In Study 812P301, 3 patients were randomized but not treated In Study 812P302, 2 patients were randomized but not treated In Study 812P303, 3 patients were randomized but not treated In Study 812P304, 1 patient was randomized but not treated

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Table 8. Patient Disposition (Studies 812P301, 812P302, 812P303, and 812P304) Study 812P301 Study 812P302 Study 812P303 Study 812P304 100 mg 200 mg Placebo 200 mg 400 mg Placebo 200 mg 400 mg Placebo 400 mg 600 mg Placebo Disposition N=154 N=161 N=159 N=99 N=105 N=104 N=107 N=100 N=103 N=100 N=99 N=97 Outcome n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Discontinued study

Adverse event 5 (3) 2 (1) 2 (1) 4 (4) 2 (2) 0 6 (6) 4 (4) 3 (3) 4 (4) 5 (5) 1 (1)

Lost to follow-up 9 (6) 6 (4) 3 (2) 6 (6) 4 (4) 2 (2) 7 (7) 8 (8) 10 (10) 5 (5) 4 (4) 5 (5) Subject 1 (1) 1 (1) 1 (1) 2 (2) 0 0 3 (3) 1 (1) 1 (1) 0 1 (1) 2 (2) noncompliant Withdrawal by 8 (5) 10 (6) 19 (12) 4 (4) 7 (7) 1 (1) 2 (2) 9 (9) 2 (2) 1 (1) 5 (5) 4 (4) parent/guardian Withdrawal by 1 (1) 0 1 (1) 3 (3) 1 (1) 2 (2) 0 1 (1) 0 2 (2) 2 (2) 0 subject Noncompliance 1 (1) 0 0 0 0 0 0 0 0 0 0 0 with study drug Other 3 (2) 1 (1) 1 (1) 1 (1) 0 3 (3) 1 (1) 0 1 (1) 0 1 (1) 0 Source: adds.xpt; Software, R. Created by the Clinical Data Scientist. Abbreviations: N = number of subjects in treatment arm; N = number of subjects in a specified population or group

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Primary Efficacy Results

The four pivotal studies evaluated the efficacy of fixed doses of SPN-812 ER, compared to placebo, in patients with ADHD: Study 301–SPN-812 ER 100 mg/day, 200 mg/day; Study 302–SPN-812 ER 200 mg/day, 400 mg/day; Study 303–SPN-812 ER 200 mg/day, 400 mg/day; and Study 304–SPN-812 ER 400 mg/day, 600 mg/day. The primary efficacy endpoint was the ADHD-RS-5 total score and was tested hierarchically, with the higher dose first. A reduction in the ADHD-RS-5 total score is evidence of improvement in ADHD symptoms. The primary objective was met in three studies (301, 302, and 303), but not in the fourth (Study 304), in which the comparison of SPN-812 ER 600 mg vs. placebo failed to reach statistical significance after adjusting for multiplicity (p=0.071). In that study, however, the comparison of SPN-812 ER 400 mg vs. placebo was nominally significant (p=0.0082). (b) (4)

In addition to the primary efficacy endpoints, key secondary endpoints were also tested in all four trials. To adjust for multiplicity, the trials utilized a sequential testing procedure to control the overall type I error rate. The multiple hypotheses involved one primary endpoint (high, low doses) and three key secondary endpoints (high, low doses). Below are the key secondary endpoints in the order in which they were tested, from highest to lowest, within each endpoint:  CGI-I score at EOS (Week 6).  Change from baseline in the Conners 3-Parent Composite T-score at EOS.  Change from baseline in the WFIRS-P total average score at EOS. A statistically significant improvement in the CGI-I was observed in Study 301 (doses 100 mg and 200 mg) and Study 303 (doses 200 mg and 400 mg), which evaluated viloxazine ER in patients ages 6 to 11 years. Similarly, a statistically significant improvement was observed on the CGI-I in doses 200 mg and 400 mg compared to placebo in Study 302, which evaluated patients ages 12 to 17 years. A statistically significant improvement was observed on the Conners 3- Parent Composite T-score and the WFIRS in Study 301 (in both dose groups). No statistically significant change on the Conners or the WFIRS was observed in the other studies. 6.2.4.1. Study 301

Primary Endpoint

The statistical reviewer confirmed the Applicant’s efficacy findings (Table 9). Fixed 100 mg/day and 200 mg/day dosages of SPN-812 ER were statistically significantly superior to placebo in the mean change from baseline in ADHD-RS-5 total score at Week 6, with least square (SE) mean treatment differences to placebo of -5.8 (1.61) (100 mg/day; p=0.0004) and -6.9 (1.58) (200 mg/day; p<0.0001), respectively.

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Table 9. Change from Baseline at Week 6 (EOS) in ADHD-RS-5 Total Score (ITT; MMRM) (Study 301) SPN-812 ER SPN-812 ER Placebo 100 mg/Day 200 mg/Day Visit Statistic N=155 N=147 N=158 Baseline Mean ± SD 43.6±7.05 45.0±6.53 44.0±6.80 EOS Mean ± SD (Week 6) 32.9±13.88 28.1±15.33 26.2±13.92 Mean ± SD (CFB) -10.7±12.98 -16.8±15.10 -17.4±13.53 EOS statistical LS mean ± SE (CFB) -10.9±1.14 -16.6±1.16 -17.7±1.12 results Difference of LS mean - -5.8±1.61 -6.9±1.58 ±SE (vs. placebo) 95% CI of difference - (-8.9, -2.6) (-10.0, -3.8) p-value (vs. placebo) - 0.0004 <0.0001 Adjusted p-value - 0.0004 <0.0001 Source: Table 11-1 of the Sponsor’s Clinical Study Report (page 62) Mean denotes raw mean (second and third rows of the table) MMRM models change from baseline in ADHD-RS-5 and comprises the baseline ADHD-RS-5 total score, age group, treatment, visit, and treatment-by-visit interaction as fixed independent variables. Abbreviations: ADHD = attention deficit/hyperactivity disorder; CFB = change from baseline; EOS = end of study; ER = extended release; ITT = intent-to-treat; LS = least square; MMRM = mixed effects model repeat measurement; N = total number of subjects; RS = rating scale; SPN = viloxazine Figure 2. LS Mean Change from Baseline in ADHD-RS-5 Total Score by Visit and Treatment Group (ITT) (Study 301)

Source: Reviewer’s result Abbreviations: ADHD = attention deficit/hyperactivity disorder; ER = extended release; LS = least squares; RS = rating scale; SPN = viloxazine 38 Integrated Review Template, version date 2019/10/16

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Key Secondary Endpoints

At the end of Week 6, a statistically significant improvement was observed on the CGI-I scale for the two SPN-812 ER dose levels (100 mg/day and 200 mg/day), compared to placebo (LS mean difference: -0.4±0.14, p<0.0001; -0.6±0.13, p=0.002). Similarly, analysis of the other key secondary variables (Conners 3-Parent Composite T-score and WFIRS-P total average score) showed statistically significantly greater improvement in the changes from baseline for all dose levels, compared to placebo, at the end of the 6-week double- blind phase. That is, Conners 3-Parent Composite T-score LS mean (SE): -4.2 (1.16), p=0.0003; -4.3±1.15, p=0.0002 and WFIRS-P total average score LS mean (SE): -0.14 (0.047), p=0.0019; -0.17 (0.046), p=0.0002. Table 10. Observed Global Severity Score (CGI-S) at Baseline and Observed Global Improvement Score (CGI-I) at Week 6 (EOS)–(ITT; ANCOVA) (Study 301) SPN-812 ER SPN-812 ER Placebo 100 mg/Day 200 mg/Day Visit Statistic N=155 N=147 N=158 Baseline Mean ± SD 4.8±0.68 4.8±0.76 4.8±0.66 EOS Mean ± SD (Week 6) 3.1±1.14 2.7±1.19 2.5±1.11 EOS Statistical results LS mean ± SE 3.1±0.10 2.7±0.10 2.6±0.09 Difference of LS mean - -0.4±0.14 -0.6±0.13 ±SE (vs. placebo) 95% CI of difference - (-0.7, -0.2) (-0.8, -0.3) p-value (vs. placebo) - 0.0020 <0.0001 Adjusted p-value - 0.0020 <0.0001 Source: Table 11-4 of the Sponsor’s Clinical Study Report (page 66) 95% CIs and p-values are from ANCOVA model with treatment as a fixed classification variable and baseline CGI-S as a covariate Abbreviations: ANCOVA = analysis of covariance; CGI-I = Clinical Global Impression – Improvement Scale; CGI-S = Clinical Global Impression – Severity of Illness Scale; CI = confidence interval; EOS = end of study; ER = extended release; LS = least square; N = total number of subjects; SPN = viloxazine Table 11. Change from Baseline at Week 6 (EOS) in the Conners 3-Parent Report Composite T-Score–(ITT; ANCOVA) (Study 301) SPN-812 ER SPN-812 ER Placebo 100 mg/Day 200 mg/Day Visit Statistic N=155 N=147 N=158 Baseline Mean ± SD 75.9±8.87 77.4±7.84 75.5±9.32 EOS Mean ± SD (Week 6) 71.2±11.36 2.7±1.19 2.5±1.11 Mean ± SD (CFB) -4.7±9.70 -9.4±11.05 -8.8±10.07 EOS statistical results LS Mean ± SE (CFB) -4.8±0.81 -9.1±0.83 -9.2±0.82 Difference of LS mean - -4.2±1.16 -4.3±1.15 ±SE (vs. placebo) 95% CI of difference - (-6.5, -1.9) (-6.6, -2.1) p-value (vs. placebo) - 0.0003 0.0002 Adjusted p-value - 0.0003 0.0002 Source: Table 11-5 of the Sponsor’s Clinical Study Report (page 68) 95% CIs and p-values are from the ANCOVA model with treatment as a fixed classification variable and baseline score as a covariate. Abbreviations: ANCOVA = analysis of covariance; CGI-I = Clinical Global Impression–Improvement scale; CGI-S = Clinical Global Impression–Severity of Illness scale; CI = confidence interval; EOS = end of study; ER = extended release; LS = least square; N = total number of subjects; SPN = viloxazine

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Table 12. Change from Baseline at Week 6 (EOS) in WFIRS-P Total Average Score–Key Secondary Analysis–(ITT; ANCOVA) (Study 301) SPN-812 ER SPN-812 ER Placebo 100 mg/day 200 mg/day Visit Statistic N=155 N=147 N=158 Baseline Mean ± SD 1.08±0.460 1.15±0.453 1.10±0.457 EOS Mean ± SD (Week 6) 0.88±0.522 0.77±0.486 0.71±0.401 Mean ± SD (CFB) -0.21±0.431 -0.38±0.467 -0.38±0.407 EOS statistical results LS Mean ± SE (CFB) -0.22±0.033 -0.36±0.033 -0.39±0.032 Difference of LS mean - -0.14±0.047 -0.17±0.046 (±SE) (vs. placebo) 95% CI of difference - (-0.24, -0.05) (-0.26, -0.08) p-value (vs. placebo) - 0.0019 0.0002 Adjusted p-value - 0.0019 0.0002 Source: Table 11-6 of the Sponsor’s Clinical Study Report (page 69) 95% CIs and p-values are from ANCOVA model with treatment as a fixed classification variable and baseline score as a covariate. Abbreviations: ANCOVA = analysis of covariance; CI = confidence interval; EOS = end of study; ER = extended release; LS = least square; N = total number of subjects; SPN = viloxazine; WFIRS-P = Weiss functional impairment rating scale–parent report Consistent results were seen for the sensitivity analyses of the primary endpoint based on multiple imputation with the missing not at random (MNAR) missing data mechanism. Reviewer’s note: This reviewer has included two figures to visualize the distribution of change in ADHD-RS-5 total score and percentage of improved subjects (Figure 3, Figure 4). Figure 3 captures the distribution of change from baseline in the ADHD-RS-5 total score. With increasing magnitude of change, there is an increasing trend in the proportion of improved subjects in the placebo group. The proportion of subjects with a treatment change of greater than -17 units in either dose group is larger than that in the placebo group. Figure 3. Percentage of Patients with a Specified Magnitude of ADHD-RS-5 Total Score Improvement at Week 6 (ITT) (Study 301)

Source: Reviewer’s result Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine

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Figure 4 shows a trend of improvement in the change from baseline in ADHD-RS-5 total score at Week 6 according to various subjective response cutoffs. Approximately 64.5%, 72.7%, and 82.9% of the patients improved at least by 3 units in the placebo, SPN-812 ER 100 mg, and 200 mg groups, respectively. Figure 4. Percentage Response (ADHD-RS-5 Total Score) for Each Treatment Group at Week 6 by Response Threshold (ITT) (Study 301)

Source: Reviewer’s result Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine 6.2.4.2. Study 302

Primary Endpoint

The reviewer confirmed the Applicant’s efficacy findings for this study. The results of the primary efficacy analysis are presented in Table 13. Adjusting for multiple-dose comparison, fixed 200 mg/day and 400 mg/day dosages of SPN-812 ER were statistically significantly superior to placebo in the mean change from baseline in ADHD-RS-5 total score at Week 6. At Week 6, the LS mean (SE) difference from placebo in the ADHD-RS-5 score was -4.5 (1.98) for SPN-812 ER 200 mg/day (p=0.0232), and -5.1 (1.93) for SPN-812 ER 400 mg/day (p=0.0091).

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Table 13. Change from Baseline at Week 6 (EOS) in ADHD-RS-5 Total Score (ITT; MMRM) (Study 302) SPN-812 ER SPN-812 ER Placebo 200 mg/Day 400 mg/Day Visit Statistic N=104 N=94 N=103 Baseline Mean ± SD 40.5±6.79 39.9±7.22 39.4±7.59 EOS Mean ± SD (Week 6) 29.2±14.74 23.4±14.17 22.8±13.78 Mean ± SD (CFB) -11.3±14.14 -16.5±14.09 -16.6±13.23 EOS statistical results LS mean ± SE (CFB) -11.4±1.37 -16.0±1.45 -16.5±1.38 Difference of LS mean - -4.5±1.98 -5.1±1.93 ±SE (vs. placebo) 95% CI of difference - (-8.4, -0.6) (-8.9, -1.3) p-value (vs. placebo) - 0.0232 0.0091 Adjusted p-value - 0.0232 0.0091 Source: Table 11-1 of the Sponsor’s Clinical Study Report (page 66). Mean denotes raw mean (second and third rows of the table); MMRM models change from baseline in ADHD-RS-5 and contains baseline ADHD-RS-5 total score, age group, treatment, visit, and treatment-by-visit interaction as fixed independent variables. Abbreviations: ADHD = attention-deficit/hyperactivity disorder; CFB = change from baseline; EOS = end of study; ER = extended release; ITT = intent-to-treat; LS = least square; MMRM = mixed effect model repeat measurement; N = total number of subjects; RS = rating scale; SPN = viloxazine Figure 5. LS Mean Change from Baseline in ADHD-RS-5 Total Score by Visit and Treatment Group (ITT) (Study 302)

Source: Reviewer’s result Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; LS = least square; RS = rating scale; SPN = viloxazine

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Key Secondary Endpoints

At the end of Week 6, a statistically significant improvement was observed on the CGI-I scale for the two SPN-812 ER doagse levels (200 mg/day and 400 mg/day), compared to placebo (LS mean: -0.5 [0.17], p<0.0042; -0.6±0.16, p=0.0003). For the two other key secondary variables (Conners 3-Parent Composite T-score and WFIRS-P total average score), the difference between either of the SPN-812 ER dose levels and placebo failed to reach statistical significance, although strong trends were observed in the contrasts between SPN-812 ER 400mg/day and placebo. Table 14. Observed Global Severity Score (CGI-S) at Baseline and Observed Global Improvement Score (CGI-I) at Week 6 (EOS), (ITT; ANCOVA) (Study 302) SPN-812 ER SPN-812 ER Placebo 200 mg/Day 400 mg/Day Visit Statistic N=104 N=94 N=103 Baseline Mean ± SD 4.6±0.65 4.6±0.70 4.6±0.64 EOS Mean ± SD (Week 6) 3.0±1.17 2.5±1.15 2.4±1.16 EOS statistical results LS mean ± SE 3.0±0.11 2.5±0.12 2.4±0.12 Difference of LS mean -0.6±0.16 (±SE) (vs. placebo) - -0.5±0.17 95% CI of difference - (-0.8, -0.2) (-0.9, -0.3) p-value (vs. placebo) - 0.0042 0.0003 Adjusted p-value - 0.0042 0.0003 Source: Table 11-4 of the Applicant’s Clinical Study Report (page 70). 95% CIs and p-values are from ANCOVA model with treatment as a fixed classification variable and baseline CGI-S as a covariate Abbreviations: ANCOVA = analysis of covariance; CGI-I = Clinical Global Impression–Improvement scale; CGI-S = Clinical Global Impression–Severity of Illness scale; CI = confidence interval; EOS = end of study; ER = extended release; ITT = intent-to-treat; LS = least square; N = total number of subjects; SPN = viloxazine Table 15. Change from Baseline at Week 6 (EOS) in the Conners 3-Parent Report Composite T-Score, (ITT; ANCOVA) (Study 302) SPN-812 ER SPN-812 ER Placebo 200 mg/Day 400 mg/Day Visit Statistic N=104 N=94 N=103 Baseline Mean ± SD 74.6±8.17 72.0±9.11 73.4±8.97 EOS Mean ± SD (Week 6) 68.3±12.06 66.2±11.44 64.7±11.53 Mean ± SD (CFB) -6.3±11.63 -5.7±10.79 -8.6±10.68 EOS statistical results LS Mean ± SE (CFB) -5.7±1.04 -6.4±1.12 -8.6±1.07 Difference of LS mean - -0.6±1.54 -2.9±1.49 (±SE) (vs. placebo) 95% CI of difference - (-3.6, 2.4) (-5.8, 0.0) p-value (vs. placebo) - 0.6854 0.0518 Adjusted p-value - 0.6854 0.0518 Source: Table 11-5 of the Applicant’s Clinical Study Report (page 71). 95% CIs and p-values are from the ANCOVA model with fixed effects for treatment and baseline score as a covariate Abbreviations: ANCOVA = analysis of covariance; CI = confidence interval; EOS = end of study; ER = extended release; ITT = intent-to-treat; LS = least square; N = total number of subjects; SPN = viloxazine

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Table 16. Change from Baseline at Week 6 (EOS) in WFIRS-P Total Average Score–Key Secondary Analysis, (ITT; ANCOVA) (Study 302) SPN-812 ER SPN-812 ER Placebo 200 mg/Day 400 mg/Day Visit Statistic N=104 N=94 N=103 Baseline Mean ± SD 1.06±0.487 1.03±0.513 1.03±0.490 EOS Mean ± SD (Week 6) 0.86±0.535 0.75±0.469 0.72±0.50 Mean ± SD (CFB) -0.20±0.492 -0.25±0.430 -0.30±0.471 EOS statistical results LS Mean ± SE (CFB) -0.19±0.041 -0.27±0.045 -0.31±0.042 Difference of LS mean - -0.08±0.061 -0.11±0.059 (±SE) (vs. placebo) 95% CI of difference - (-0.20, 0.04) (-0.23, 0.00) p-value (vs. placebo) - 0.2062 0.0519 Adjusted p-value - -- 0.0519 Source: Table 11-6 of the Applicant’s Clinical Study Report (page 72). 95% CIs and p-values are from the ANCOVA model with fixed effects for treatment and baseline score as a covariate Abbreviations: ANCOVA = analysis of covariance; CI = confidence interval; EOS = end of study; ER = extended release; ITT = intent-to-treat; LS = least square; N = total number of subjects; SPN = viloxazine; WFIRS-P = Weiss functional impairment rating scale–parent report Sensitivity analysis of the primary endpoint based on multiple imputation with the MNAR missing data mechanism were consistent with the main efficacy conclusions. Reviewer’s note: As shown in Figure 6, with increased change from baseline in ADHD-RS-5, more subjects are allocated in either dose groups (SPN-812 200 mg or 400 mg). Figure 7 presents the empirical percentage response for each treatment group at Week 6 by various response cutoffs. There was a consistent improvement trend in the change from baseline in ADHD-RS-5 total score at Week 6 for several arbitrary response magnitudes. Approximately 64.7% (placebo), 73.9% (SPN-812 200 mg), and 79.6% (SPN-812 400 mg) of subjects in the ITT population exhibited a greater than 3-point improvement in response.

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Figure 6. Percentage of Patients with a Specified Magnitude of ADHD-RS-5 Total Score Improvement at Week 6 (ITT) (Study 302)

Source: Reviewer’s result Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine Figure 7. Percentage Response (ADHD-RS-5 Total Score) for Each Treatment Group at Week 6 by Response Threshold (ITT) (Study 302)

Source: Reviewer’s result Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine

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6.2.4.3. Study 303

Primary Endpoint

The reviewer confirmed the Applicant’s efficacy findings for this study. The results of the primary efficacy analysis are presented in Table 17. Adjusting for multiple-dose comparison, fixed 200 mg/day and 400 mg/day dosages of SPN-812 ER were statistically significantly superior to placebo in the mean change from baseline in ADHD-RS-5 total score at Week 6 (LS mean difference -6.0 [2.05], 0.0063; -5.8 [2.11], p=0.0063). Table 17. Change from Baseline at Week 8 (EOS) in ADHD-RS-5 Total Score (ITT; MMRM) (Study 303) SPN-812 ER SPN-812 ER Placebo 200 mg/Day 400 mg/Day Visit Statistic N=97 N=107 N=97 Baseline Mean ± SD 43.5±6.79 43.8±6.54 45.0±6.55 EOS Mean ± SD (Week 8) 32.8±15.10 26.5±14.96 27.3±15.02 Mean ± SD (CFB) -11.0±13.64 -17.1±14.89 -17.6±14.36 EOS statistical results LS mean ± SE (CFB) -11.7±1.48 -17.6±1.43 -17.5±1.52 Difference of LS mean - -6.0±2.05 -5.8±2.11 (±SE) (vs. placebo) 95% CI of difference - (-10.0, -1.9) (-9.9, -1.7) p-value (vs. placebo) - 0.0038 0.0063 Adjusted p-value - 0.0063 0.0063 Source: Table 11-1 of the Sponsor’s Clinical Study Report (page 65) Mean denotes raw mean (second and third rows of the table) MMRM models change from baseline in ADHD-RS-5 and contains baseline ADHD-RS-5 total score, age group, treatment, visit, and treatment-by-visit interaction as fixed independent variables. Abbreviations: ADHD = attention-deficit hyperactivity disorder; CFB = change from baseline; CI = confidence interval; EOS = end of study; ER = extended release; ITT = intent-to-treat; LS = least square; MMRM = mixed effect model repeat measurement; N = total number of subjects; RS = rating scale; SPN = viloxazine

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Figure 8. LS Mean Change from Baseline in ADHD-RS-5 Total Score by Visit and Treatment Group (ITT) (Study 303)

Source: Reviewer’s result Abbreviations: ADHD = attention deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; LS = ; RS = rating scale; SPN = viloxazine

Key Secondary Endpoints

At the end of Week 6, a statistically significant improvement was observed on the CGI-I scale for the two SPN-812 ER dose levels (200 mg/day and 400 mg/day), compared to placebo (LS mean [±SE] -0.5±0.17, p=0.0009; -0.4±0.17, p=0.0009). The SPN-812 ER 200 mg/day group showed numerical improvement compared to placebo (LS mean -3.8 (1.39); p=0.0064) in the change from baseline in Conners 3-Parent Composite T-score at Week 8, but the change failed to reach statistical significance when adjusted for multiplicity (p=0.0917). No statistically significant change on the Conners 3-Composite T-score was observed for the 400 mg/day group. The difference between either of the SPN-812 ER dose levels and placebo failed to reach statistical significance for the WFIRS-P total average score.

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Table 18. Observed Global Severity Score (CGI-S) at Baseline and Observed Global Improvement Score (CGI-I) at Week 8 (EOS), (ITT; ANCOVA) (Study 303) SPN-812 ER SPN-812 ER Placebo 200 mg/day 400 mg/day Visit Statistic N=97 N=107 N=97 Baseline Mean ± SD 4.8±0.69 4.8±0.70 4.8±0.74 EOS Mean ± SD (Week 6) 3.1±1.26 2.6±1.17 2.6±1.08 EOS statistical results LS mean ± SE 3.1±0.12 2.6±0.12 2.6±0.12 Difference of LS mean - -0.5±0.17 -0.4±0.17 (±SE) (vs. placebo) 95% CI of difference - (-0.8, -0.2) (-0.8, -0.1) p-value (vs. placebo) - 0.0028 0.0099 Adjusted p-value - 0.0099 0.0099 Source: Table 11-4 of the Applicant’s Clinical Study Report (page 69). 95% CIs and p-values are from the ANCOVA model with treatment as a fixed classification variable and baseline CGI-S as a covariate. Abbreviations: ANCOVA = analysis of covariance; CGI-I = Clinical Global Impression–Improvement Scale; CGI-S = Clinical Global Impression–Severity of Illness Scale; CI = confidence interval; EOS = end of study; ER = extended release; ITT = intent-to-treat; LS = least squares; N = total number of subjects; SPN = viloxazine Table 19. Change from Baseline at Week 8 (EOS) in the Conners 3–Parent Report Composite T- Score, (ITT; ANCOVA) (Study 303) SPN-812 ER SPN-812 ER Placebo 200 mg/Day 400 mg/Day Visit Statistic N=97 N=107 N=97 Baseline Mean ± SD 77.1±8.13 76.0±8.11 77.9±8.23 EOS Mean ± SD (Week 6) 71.7±9.84 67.2±10.26 69.6±11.31 Mean ± SD (CFB) -5.3±10.08 -8.6±10.60 -8.2±10.22 EOS statistical results LS Mean ± SE (CFB) -5.3±1.00 -9.1±0.96 -7.8±1.06 Difference of LS mean - -3.8±1.39 -2.5±1.46 (±SE) (vs. placebo) 95% CI of difference - (-6.5, -1.1) (-5.3, 0.4) p-value (vs. placebo) - 0.0064 0.0917 Adjusted p-value - 0.0917 0.0917 Source: Table 11-5 of the Applicant’s Clinical Study Report (page 70). 95% CIs and p-values are from the ANCOVA model with fixed effects for treatment and baseline score as a covariate. Abbreviations: ANCOVA = analysis of covariance; CFB = change from baseline; CI = confidence interval; EOS = end of study; ER = extended release; ITT = intent-to-treat; LS = least squares; N = total number of subjects; SPN = viloxazine Table 20. Change from Baseline at Week 8 (EOS) in WFIRS-P Total Average Score–Key Secondary Analysis, (ITT; ANCOVA) (Study 303) SPN-812 ER SPN-812 ER Placebo 200 mg/Day 400 mg/Day Visit Statistic N=97 N=107 N=97 Baseline Mean ± SD 1.11±0.457 1.08±0.493 1.17±0.482 EOS Mean ± SD (Week 6) 0.87±0.469 0.74±0.464 0.82±0.517 Mean ± SD (CFB) -0.23±0.485 -0.33±0.470 -0.34±0.429 EOS statistical results LS Mean ± SE (CFB) -0.24±0.042 -0.35±0.041 -0.33±0.044 Difference of LS mean - -0.11±0.059 -0.08±0.061 (±SE) (vs. placebo) 95% CI of difference - (-0.22, 0.01) (-0.20, 0.04) p-value (vs. placebo) - 0.0651 0.1680 Adjusted p-value - -- -- Source: Table 11-6 of the Applicant’s Clinical Study Report (page 72). 95% CIs and p-values are from the ANCOVA model with fixed effects for treatment and baseline score as a covariate. Abbreviations: ANCOVA = analysis of covariance; CBF = change from baseline; EOS = end of study; ER = extended release; ITT = intent-to-treat; LS = least squares; N = total number of subjects; SPN = viloxazine; WFIRS-P = Weiss Functional Impairment Rating Scale-Parent Report;

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The results of the sensitivity analysis (multiple imputation based on MNAR) of the primary endpoint yielded the same conclusions as those of the primary efficacy analysis. Reviewer’s note: Figure 9 shows the distribution of the magnitude of change in ADHD-RS-5. The proportion of subjects who experienced improvement in ADHD-RS-5 scores in the SPN-812 200 mg and 400 mg dose groups was greater than that in the placebo group. Figure 10 shows the proportion of patients who had an improvement based on various ADHD- RS-5 response thresholds across the treatment groups at Week 6. For example, approximately 60.9% (placebo), 73.7% (SPN-812 200 mg), and 76.5% (SPN-812 400 mg) of subjects showed a greater than 3-point improvement in ADHD-RS-5 score. Figure 9. Percentage of Patients with a Specified Magnitude of ADHD-RS-5 Total Score Improvement at Week 8 (ITT) (Study 303)

Source: Reviewer’s result Abbreviations: ADHD = attention deficit hyperactivity disorder; ER = extended release; FAS = full analysis set; ITT = intent-to-treat; N = total number of subjects; RS = rating scale; SPN = viloxazine

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Figure 10. Percentage Response (ADHD-RS-5 Total Score) for Each Treatment Group at Week 8 by Response Threshold (ITT) (Study 303)

Source: Reviewer’s result Abbreviations: ADHD = attention deficit/hyperactivity disorder; ER = extended release; FAS = full analysis set; ITT = intent-to-treat; N = total number of subjects; RS = rating scale; SPN = viloxazine 6.2.4.4. Study 304

Primary Endpoint

The reviewer confirmed the Applicant’s efficacy findings for this study. The results of the primary efficacy analysis are presented in Table 21. Adjusting for multiple comparisons (through the prespecified testing sequence starting with the high dose), none of the SPN-812 ER dosing group was statistically significantly better than placebo in the change from baseline in ADHD- RS-5 total score at end of treatment (Week 7). A nominally significant improvement was, however, observed for the 400 mg/day dosing group, compared to placebo. At Week 7, the LS mean (SE) difference from placebo in ADHD-RS-5 score was -5.1 (1.93) for SPN-812 ER 400 mg/day (p=0.071) and -3.5 (1.93) for SPN-812 ER 600 mg/day (p=0.071).

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Table 21. Change from Baseline at Week 7 (EOS) in ADHD-RS-5 Total Score (ITT; MMRM) (Study 304) SPN-812 ER SPN-812 ER Placebo 400 mg/Day 600 mg/Day Visit Statistic N=96 N=99 N=97 Baseline Mean ± SD 38.8±8.06 41.2±7.80 39.8±8.34 EOS Mean ± SD (Week 7) 25.5±12.95 21.8±13.60 23.2±13.15 Mean ± SD (CFB) -13.0±13.07 -19.1±13.77 -16.3±14.06 EOS statistical results LS mean ± SE (CFB) -13.2±1.38 -18.3±1.36 -16.7±1.39 Difference of LS mean - -5.1±1.93 -3.5±1.93 (±SE) (vs. placebo) 95% CI of difference - (-8.9, -1.3) (-7.3, 0.3) p-value (vs. placebo) - 0.0082 0.071 Adjusted p-value - 0.071 0.071 Source: Table 14 of the Applicant’s Clinical Study Report (page 93). Mean denotes raw mean (second and third rows of the table) MMRM models change from baseline in ADHD-RS-5 and comprises baseline ADHD-RS-5 total score, age group, treatment, visit, and treatment-by-visit interaction as fixed independent variables. Abbreviations: ADHD = attention deficit/hyperactivity disorder; CBF = change from baseline; CI = confidence interval; EOS = end of study; ER = extended release; ITT = intent-to-treat; LS = least squares; MMRM = mixed effect model repeat measurement; N = total number of subjects; SPN = viloxazine Figure 11. LS Mean Change from Baseline in ADHD-RS-5 Total Score by Visit and Treatment Group (ITT) (Study 304)

Source: Reviewer’s result Abbreviations: ADHD = attention deficit hyperactivity disorder; ER = extended release; ITT = intent-to-treat; LS = least squares; MMRM = mixed effect model repeat measurement; RS = rating scale; SPN = viloxazine

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Key Secondary Endpoints

At Week 7, patients in the SPN-812 ER 400 mg/day dosing group experienced a nominally statistically significantly greater improvement on the CGI-I scale, compared to placebo (LS mean -0.5 [0.17]; p=0.0051), but this endpoint was lower in the testing hierarchy than the first key secondary endpoint (CGI-I for SPN-812 ER 600 mg/day). The difference between either of the SPN-812 ER dose levels and placebo failed to reach statistical significance for the Conners 3-Parent Composite T-score and the WFIRS-P total average score. Table 22. Observed CGI-S at Baseline and Observed CGI-I at Week 8 (EOS), (ITT; ANCOVA) (Study 304) SPN-812 ER SPN-812 ER Placebo 400 mg/Day 600 mg/Day Visit Statistic N=96 N=99 N=97 Baseline Mean ± SD 4.5±0.66 4.8±0.69 4.6±0.69 EOS Mean ± SD (Week 6) 2.9±1.11 2.3±1.17 2.6±1.16 EOS statistical results LS mean ± SE 2.9±0.12 2.4±0.12 2.6±0.12 Difference of LS mean - -0.5±0.17 -0.3±0.17 (±SE) (vs. placebo) 95% CI of difference - (-0.8, -0.1) (-0.6, 0.1) p-value (vs. placebo) - 0.0051 0.0995 Adjusted p-value - -- -- Source: Table 11-4 of the Applicant’s Clinical Study Report (page 68). 95% CIs and p-values are from the ANCOVA model with treatment as a fixed classification variable and baseline CGI-S as a covariate. Abbreviations: ANCOVA = analysis of covariance; CGI-I = Clinical Global Impression–Improvement Scale; CGI-S = Clinical Global Impression–Severity of Illness Scale; CI = confidence interval; EOS = end of study; ER = extended release; ITT = intent-to-treat; LS = least squares; N = total number of subjects; SPN = viloxazine Table 23. Change from Baseline at Week 8 (EOS) in the Conners 3-Parent Report Composite T-Score, (ITT; ANCOVA) (Study 304) SPN-812 ER SPN-812 ER Placebo 400 mg/Day 600 mg/Day Visit Statistic N=96 N=99 N=97 Baseline Mean ± SD 73.1±8.91 73.2±8.87 73.9±8.82 EOS Mean ± SD (Week 6) 67.4±9.48 65.7±10.28 66.7±9.96 Mean ± SD (CFB) -5.4±9.04 -7.3±8.97 -7.1±8.97 EOS statistical results LS Mean ± SE (CFB) -5.6±0.89 -7.5±0.87 -6.9±0.88 Difference of LS mean - -1.9±1.26 -1.3±1.25 (±SE) (vs. placebo) 95% CI of difference - (-4.3, 0.6) (-3.7, 1.2) p-value (vs. placebo) - 0.1377 0.3130 Adjusted p-value - -- -- Source: Table 11-5 of the Applicant’s Clinical Study Report (page 70). 95% CIs and p-values are from ANCOVA model with fixed effects for treatment and baseline score as a covariate. Abbreviations: ANCOVA = analysis of covariance; CBF = change from baseline; CI = confidence interval; EOS = end of study; ER = extended release; ITT = intent-to-treat; LS = least squares; N = total number of subjects; SPN = viloxazine

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Table 24. Change from Baseline at Week 8 (EOS) in WFIRS-P Total Average Score–Key Secondary Analysis, (ITT; ANCOVA) (Study 304) SPN-812 ER SPN-812 ER Placebo 400 mg/Day 600 mg/Day Visit Statistic N=96 N=99 N=97 Baseline Mean ± SD 0.97±0.480 0.96±0.442 0.99±0.450 EOS Mean ± SD (Week 6) 0.72±0.427 0.63±0.341 0.74±0.419 Mean ± SD (CFB) -0.22±0.419 -0.29±0.340 -0.23±0.417 EOS statistical results LS Mean ± SE (CFB) -0.23±0.035 -0.32±0.034 -0.23±0.035 Difference of LS mean - -0.09±0.049 0.00±0.050 (±SE) (vs. placebo) 95% CI of difference - (-0.19, 0.01) (-0.10, 0.10) p-value (vs. placebo) - 0.0698 0.9756 Adjusted p-value - -- -- Source: Table 11-6 of the Applicant’s Clinical Study Report (page 71). 95% CIs and p-values are from the ANCOVA model with fixed effects for treatment and baseline score as a covariate. Abbreviations: ANCOVA = analysis of covariance; CBF = change from baseline; CI = confidence interval; EOS = end of study; ER = extended release; ITT = intent-to-treat; LS = least squares; N = total number of subjects; SPN = viloxazine; WFIRS-P = Weiss functional impairment rating scale–parent report The sensitivity analysis (multiple imputation based on MNAR) of the primary endpoint yielded the same conclusions as the primary efficacy analysis result. Reviewer’s note: Figure 12, an exploratory plot of the distribution of the magnitude of change in ADHD-RS-5 score, shows a high proportion of subjects in the placebo group with improved ADHD-RS-5 scores at Week 7. Figure 13 displays the proportion of subjects who met a specific threshold (greater than or equal to a response cutoff). Approximately 72% (placebo), 85.7% (SPN-812 400 mg), and 79% (SPN- 812 600 mg) of subjects showed a greater than 3-point improvement in ADHD-RS-5 score at Week 7. More subjects in the SPN-812 400 mg group than in the placebo group or the SPN-812 600 mg group showed a consistent improvement in ADHD-RS-5 score. Figure 12. Percentage of Patients with a Specified Magnitude of ADHD-RS-5 Total Score Improvement at Week 7 (ITT) (Study 304)

Source: Reviewer’s result Abbreviations: ADHD = attention deficit hyperactivity disorder; ER = extended release; FAS = full analysis set; ITT = intent-to-treat; N = total number of subjects; RS = rating scale; SPN = viloxazine

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Figure 13. Percentage Response (ADHD-RS-5 Total Score) for Each Treatment Group at Week 7 by Response Threshold (ITT) (Study 304)

Source: Reviewer’s result Abbreviations: ADHD = attention deficit hyperactivity disorder; ER = extended release; FAS = full analysis set; ITT = intent-to-treat; N = total number of subjects; RS = rating scale; SPN = viloxazine

6.2.5. Integrated Assessment of Effectiveness The controlled phase 3 studies provide evidence of effectiveness for the 100 mg, 200 mg, and 400 mg doses of viloxazine in pediatric patients ages 6 to 11 years, and for the 200 mg and 400 mg doses of viloxazine in patients ages 12 to 17 years. There is no evidence of a greater efficacy of the 600 mg dose of viloxazine (b) (4) Although the CGI-I may be vulnerable to recall bias, the positive CGI-I results across dose groups in Studies 812P301, 812P302, and 812P303 provide additional support for the clinical meaningfulness of the primary efficacy results. 6.3. Key Review Issues Relevant to the Evaluation of Benefit (b) (4)

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(b) (4)

6.4. Potential Risks or Safety Concerns Based on Drug Class or Other Drug-Specific Factors Viloxazine ER is a norepinephrine reuptake inhibitor. As described in Section 3, another norepinephrine reuptake inhibitor, atomoxetine, is indicated for the treatment of ADHD. Safety concerns associated with atomoxetine include cardiovascular adverse events, suicidal ideation and other psychiatric adverse events, negative effects on growth, and liver injury. The safety review included an assessment of these safety concerns with use of viloxazine ER. 7. Risk and Risk Management 7.1. Potential Risks or Safety Concerns Based on Nonclinical Data The nonclinical safety studies in this application included in vitro and in vivo pharmacology and pharmacokinetic studies, genotoxicity studies, single- and multiple-dose toxicity studies, reproductive/developmental studies, and carcinogenicity studies. The major safety-related findings are summarized below. The detailed evaluation of risk is discussed in Section 7.6. Full reviews for all nonclinical studies are located in Section III.13.2.

Pharmacology

Viloxazine is a norepinephrine reuptake inhibitor (see Sections Error! Reference source not found. and III.14.2). Based on its pharmacology, viloxazine could induce noradrenergic effects in the cardiovascular system. See Section 7.6.4 for a detailed evaluation of the risk of heart rate and blood pressure changes.

Pharmacokinetics

There are substantial species differences in the metabolism of viloxazine between the nonclinical species (rats and dogs) and humans. In primary hepatocytes, viloxazine is extensively metabolized in rat hepatocytes, moderately metabolized in dog hepatocytes, and minimally metabolized in human hepatocytes. There are no unique human metabolites. The in vivo metabolic profile was quantitatively compared between the rat and human. In rat, viloxazine is extensively metabolized, with desethyl viloxazine as the major circulating metabolite, accounting for up to 60% of total drug-related exposure; the parent drug accounts for only ~10% to 20% of total drug-related exposure. In contrast, in human, there is limited metabolism and unchanged viloxazine is the major circulating entity in plasma, accounting for ~60% of total drug-related exposure, as well as glucuronidated 5-hydroxy-viloxazine, which accounts for ~10% to 16%. (The latter is present as a minor metabolite in rat). Other minor human metabolites of viloxazine include unconjugated 4- and 5-monohydroxylated viloxazine and glucuronidated N- carboxylated-viloxazine, accounting for <10% of total drug-related exposure.

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It should be noted that despite the differences in the metabolic profiles, the exposure level to both the parent drug and its major human metabolite (glucuronidated-5-hydroxy-viloxazine) are adequately represented and characterized in rat (for a detailed comparison, see Section III.13.2.3 Pharmacokinetics).

General Toxicology

Drug-related Convulsions

In general toxicology and/or carcinogenicity studies in all species tested (rat, mouse, and dog), viloxazine caused multiple central nervous system (CNS) effects, ranging from clinical signs consistent with CNS depression and ataxia at lower doses, to and convulsions or even deaths at higher doses. Specifically, viloxazine caused convulsions at doses approximately equal to or slightly higher than the maximum recommended human dose (MRHD) of 400 mg, based on mg/m2 body surface area in children1, and the threshold for convulsions decreased with repeated viloxazine treatment. These CNS effects are likely associated with the adrenergic pharmacology of the drug; these effects did not cause histopathology lesions in the brain. See Section 7.1 Risk of Seizure for details of the safety evaluation.

Drug-related Liver Findings

In all three species (rat, mouse, and dog), repeat administration of viloxazine caused dose- dependent hepatocellular hypertrophy and/or vacuolation in the liver. In addition, viloxazine caused hepatocellular eosinophilic bodies or inclusion bodies in dog. Vacuolation was due to lipid accumulation, and inclusion bodies were likely due to hypertrophic endoplasmic reticulum. These changes were reversible. See Section 7.6.5 Risk of Liver Injury for a detailed safety evaluation.

Drug-related Decreases in Body Weight, Weight Gain, and Food Consumption

Viloxazine treatment caused dose-dependent decreases in body weight, weight gain, and/or food consumption. The decreases were more profound at higher doses, particularly during the first few weeks after treatment initiation and were mostly reversible after dose was reduced or stopped (recovery). These effects are likely associated with the adrenergic pharmacology of the drug. Body weight and food consumption are clinically monitorable; therefore, moderate decreases in body weight and food consumption do not represent an unacceptable risk.

Genotoxicity and Carcinogenicity

Viloxazine was not genotoxic in a battery of genotoxicity tests. It was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro mammalian chromosomal aberration assay (human peripheral blood) or the in vivo rat bone marrow micronucleus assay.

1 Because the proposed indication is for pediatric population only (ADHD patients ages 6 to 17 years), body surface area (mg/m2)-based safety margins are calculated using average child body weight of 20 kg and conversion factor Km of 25.

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Viloxazine did not increase the incidence of tumors in rats treated orally for 2 years at doses of 22, 43, and 87 mg/kg/day. The highest dose of 87 mg/kg/day is approximately equal to the MRHD of 400 mg, based on mg/m2 in children. Viloxazine did not increase the incidence of tumors in Tg.rasH2 mice treated orally for 26 weeks at doses of 4.3, 13, and 43 mg/kg/day. 7.2. Potential Safety Concerns Identified Through Postmarket Experience Immediate-release viloxazine was authorized as a treatment for depression in the European Union from 1976 to 2008. The team reviewed available postmarketing information from EudraVigilance, the European Medicines Agency’s publicly available system for tracking suspected adverse drug reactions, and from Vigibase, the World Health Organization’s global Individual Case Safety Report database. Although viloxazine has never been approved or marketed in the United States, the FDA Adverse Event Reporting System (FAERS) was also queried for any relevant case reports. The Division of Pharmacovigilance assisted with identifying postmarketing adverse drug reaction reports.

EudraVigilance

A total of 37 individual case reports is included in the European Database of Suspected Adverse Drug Reactions (EudraVigilance) as of April 25, 2020. Males accounted for 20 cases and females for 17 cases. No pediatric cases were reported. Most (34/37) cases originated in France. The most common system organ classes (SOCs) represented were Nervous System Disorders and Hepatobiliary Disorders (Figure 17). Among patients who reported Nervous System Disorders, the event terms included somnolence, balance disorder, cerebrovascular accident, dizziness, headache, serotonin syndrome, and Wernicke’s encephalopathy. Of note, there were also two reports of . In addition, there were reports of coma in 3 patients; 1 of these cases was fatal. Among patients who reported Hepatobiliary Disorders, the event terms included cholestasis, hepatitis, hepatitis cholestatic, hepatitis toxic, hepatocellular injury, and hyperbilirubinemia. Two of the reported cases of hepatitis were fatal. Cardiac disorders and hypertension were not reported. Hypotension was reported in 3 cases. One completed suicide was reported. No other reports of suicidal ideation or behavior are included in the database. Interpretation of the data from the EudraVigilance database is hampered by several factors. First, clinical narratives were not available for the case reports included in the EudraVigilance database. Second, the database may contain duplicate reports. In addition, the total number of patients exposed to immediate-release viloxazine is not known, so the true frequency of adverse reactions cannot be calculated. Finally, adverse reactions associated with the immediate-release formulation of viloxazine may not necessarily occur with viloxazine extended-release. However, given the reports of hepatobiliary adverse reactions, including of fatal cases, data related to the effect of viloxazine ER on liver assessments were specifically reviewed and are summarized in

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Section 7.6.5. Seizures were reported in the postmarketing period; Section 7.6.1 also includes a review of the data related to the risk of seizure with viloxazine ER exposure. Despite the limitations of the available data, the fact that suicidal behavior was rarely reported is reassuring given the concern about the higher rate of suicidal ideation and behavior in the viloxazine ER clinical trials.

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Figure 17. Number of Individual Cases by Reaction Group–EudraVigilance Database

Source: EudraVigilance Database - http://www.adrreports.eu

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Vigibase

Vigibase contains 440 adverse drug reaction reports from the years 1976 to 2014. Female patients accounted for 59% of the reports. In total, three pediatric reports are included in the database (one report in a patient 0 to 27 days of age and two reports in patients ages 12 to 17 years). Nervous system disorders, Gastrointestinal disorders, Psychiatric disorders, Skin and subcutaneous tissue disorders, and Hepatobiliary disorders were most common (Figure 18). Figure 18. Adverse Drug Reactions Reported to Vigibase–1976 to 2014

Source: http://www.vigiaccess.org Adverse events of special interest in this application include seizures, cardiovascular effects, and psychiatric adverse events. The Vigibase database contains a total of 31 reports of seizure, including the following event terms: seizure (19 reports), epilepsy (6 reports), generalized tonic clonic seizure (5 reports), and petit mal seizure (1 report). The most commonly reported psychiatric adverse event was confusional state (35 reports), followed by agitation (12 reports). Of note, the database includes one report of suicide attempt but no other reports of suicidal ideation or behavior. Tachycardia was the most commonly reported cardiac disorder (9 reports), and orthostatic hypotension was the most commonly reported vascular disorder (9 reports). Hypertension, hypotension, palpitations, and bradycardia were also reported.

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FAERS

From 1997 to 2016, a total of 35 reports involving viloxazine hydrochloride were included in the FAERS database, including 33 serious reports and 5 deaths. The FAERS database may contain duplicate reports. Suspected drug reactions in the Nervous System Disorders, General Disorders and Administration, and Investigations reaction groups were most common (Figure 19). However, although viloxazine is listed among the suspect product active ingredients in these 35 reports, viloxazine was not the suspect product in any report, or the sole suspect active ingredient in any report. In each report, multiple suspect active ingredients are listed. In three of the reports of death, the suspect product was ceftriaxone. In the other two reports of death, the suspect products were chlorazepate and labetalol. Of note, the database includes two reports of seizure and six reports of epilepsy. See Section 7.6.1 for a discussion of these cases. These case reports were confounded by the presence of other medications and medical illness; the seizure events could not clearly be attributed to viloxazine. Similarly, the reports of liver injury were also confounded; see Section 7.6.5 for a full discussion of data related to viloxazine ER exposure and hepatobiliary adverse events and laboratory assessments. Figure 19. Suspected Adverse Reactions by Reaction Groups Reported to the FAERS Database– 1997 to 2016

Source: https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting- system-faers-public-dashboard Abbreviation: FAERS = FDA Adverse Event Reporting System

Summary of Postmarketing Safety Signals

Although immediate-release viloxazine was authorized in Europe for more than 30 years for the treatment of major depressive disorder, few data about adverse reactions are available in worldwide postmarketing databases. The postmarketing reports include primarily adult data. Notable adverse events reported in the postmarketing period include seizures and liver injury.

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However, the available reports of these events are confounded by the presence of other possibly contributory factors. In addition, the true frequency of these events among patients exposed to viloxazine is unknown. Of note, there are few reports of suicidal ideation and behavior in the postmarketing databases, which may be somewhat reassuring given that patients with major depressive disorder could be more vulnerable to suicidal ideation. The limitations of the data nonetheless preclude any clear determination of the risk of suicidal ideation and behavior with viloxazine. 7.3. FDA Approach to the Safety Review The safety review focused primarily on the four phase 3 placebo-controlled efficacy and safety studies (812P301, 812P302, 812P303, and 812P304). Adverse events were examined for two age groups (ages 6 to 11 and 12 to 17 years) and four dose arms (100 mg, 200 mg, 400 mg, and 600 mg). The vital signs, laboratory, electrocardiogram, and C-SSRS databases for the phase 3 trials were also analyzed. Convulsions occurred in multiple species in nonclinical studies, and so seizures and seizure-like events were considered adverse events of special interest in the development program. Based on the mechanism of action and the potential for stimulation of the adrenergic system, cardiovascular adverse events were also examined closely. This drug is intended for use in the pediatric population, so effects on weight and growth, both short- and long-term, were investigated. Finally, given the frequent psychiatric comorbidities of ADHD, psychiatric adverse events were also analyzed. In addition to data from the phase 3 studies, the safety review considered adverse events and other supporting safety data from Study 812P202, a phase 2 dose-finding study. Study 812P310, an open-label safety extension, was the primary source of long-term safety data. Though this study did not include controlled data, long-term trends in vital signs, growth parameters, and laboratory assessments were examined. Immediate-release viloxazine was previously approved in Europe for the treatment of depression. Therefore, publicly available European postmarketing data for viloxazine were also reviewed. The Applicant submitted a thorough QT study, which was reviewed by the QT/IRT consultation team. In addition, the Controlled Substance Staff (CSS) reviewed the data for drug dependence and liability signals. 7.4. Adequacy of the Clinical Safety Database The safety database was comprehensive, and adequate to assess the safety of viloxazine ER in pediatric patients ages 6 to 17 years with ADHD. A summary of the exposures in the phase 3 controlled studies is shown in Table 28. The median duration of exposure in these studies was approximately 6 weeks. The duration of exposure to study drug was balanced between the viloxazine ER treatment groups and the placebo groups.

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Table 28. Duration of Exposure, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) Ages 6 to 11 Years Ages 12 to 17 Years (812P301 and 812P303) (812P302 and 812P304) Total 100 mg 200 mg 400 mg TX Placebo 200 mg 400 mg 600 mg TX Placebo TX Placebo Variable N=154 N=268 N=100 N=522 N=262 N=99 N=205 N=99 N=403 N=201 N=925 N=463 Duration of exposure (weeks) Mean (SD) 7.0 (6.6) 6.5 (2.1) 6.9 (2.5) 6.7 (4.0) 6.5 (3.2) 5.3 (1.8) 6.1 (1.6) 6.2 (2.0) 6.0 (1.8) 6.2 (1.4) 6.4 (3.3) 6.4 (2.6) Median 6.1 6.1 8.0 6.1 6.1 6.1 6.3 7.1 6.3 6.3 6.1 6.3 (min, max) (0.1, 45.4) (0.1, 20.4) (0.1, 9.0) (0.1, 45.4) (0.1, 38.0) (0.1, 7.0) (0.1, 8.9) (0.1, 8.4) (0.1, 8.9) (0.1, 8.4) (0.1, 45.4) (0.1, 38.0) Subjects treated, by duration (weeks), n (%) <1 3 (2) 5 (2) 4 (4) 12 (2) 7 (3) 7 (7) 5 (2) 3 (3) 15 (4) 3 (2) 27 (3) 10 (2) 1 to <3 11 (7) 8 (3) 7 (7) 26 (5) 19 (7) 4 (4) 13 (6) 8 (8) 25 (6) 8 (4) 51 (6) 27 (6) 3 to <6 24 (16) 32 (12) 10 (10) 66 (13) 29 (11) 19 (19) 17 (8) 8 (8) 44 (11) 21 (10) 110 (12) 50 (11) 6 to <9 108 (70) 219 (82) 78 (78) 405 (78) 202 (77) 69 (70) 170 (83) 80 (81) 319 (79) 169 (84) 724 (78) 371 (80) 9 to <12 0 1 (0.4) 1 (1) 2 (0.4) 2 (1) 0 0 0 0 0 2 (0.2) 2 (0.4) Missing TX end 8 (5) 3 (1) 0 11 (2) 3 (1) 0 0 0 0 0 11 (1) 3 (1) date Source, adex.xpt; Software, Python. Created by the Clinical Data Scientist and Clinical Review Team. Abbreviations: N = number of subjects in treatment arm; n = number of subjects with given treatment duration; TX = treatment

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According to the International Conference on Harmonisation (ICH) EI Guidance, for chronically administered medications, the safety database should include at least 1500 individuals exposed to the investigational product in short-term trials, 300 to 600 individuals with at least 6 months of exposure, and 100 individuals with at least 1 year of exposure. At the time of the 120-day safety update, 1593 individuals had been exposed to viloxazine ER. Of the patients who received viloxazine ER in the long-term safety extension study (812P310), 429 were exposed for <6 months, 340 for 6 to 12 months, and 347 were exposed for ≥12 months. The duration of exposure was similar in the child and adolescent age groups (Table 29). Table 29. Duration of Exposure to Viloxazine ER 6-11 Years 12-17 Years Total Parameter (N=668) (N=448) (N=1116) Patients treated, by duration, n (%) <6 months 231 (35%) 198 (44%) 429 (38%) 6 to 12 months 203 (30%) 137 (31%) 340 (31%) ≥12 months 234 (35%) 113 (25%) 347 (31%) Source: 812P310 adsl. Data cutoff March 5, 2020. Created by (b) (4) and the Clinical Reviewer. Abbreviations: N = number of subjects in the group; n = number of subjects with a given treatment duration 7.5. Safety Findings and Safety Concerns Based on Review of the Clinical Safety Database The submitted safety data for viloxazine ER in pediatric patients ages 6 to 17 years were adequate. The safety profile of viloxazine ER in this population is acceptable for the intended use. Rates of discontinuation because of adverse events and serious adverse events were low. No deaths occurred in the development program. The most common treatment-emergent adverse events were somnolence/sedation, headache, fatigue, decreased appetite, abdominal pain, upper respiratory infection, nausea, and vomiting. Transaminase values were more likely to shift from within the reference range to above the reference range in patients receiving viloxazine; however, transaminase elevations were modest, and no cases of drug-induced liver injury were identified. Viloxazine ER was otherwise not associated with other clinically meaningful changes in laboratory values. Viloxazine ER was associated with higher rates of suicidal ideation and behavior, increases in heart rate and diastolic blood pressure, and may be associated with slowed weight gain. These risks are reviewed more fully in Section 7.6 and can be described in labeling to support safe use of viloxazine in the intended population. 7.5.1. Overall Adverse Event Summary Approximately 52% of viloxazine ER–treated patients experienced a TEAE, compared to approximately 37% of placebo-treated patients (Table 30). The incidence of treatment-emergent adverse events (TEAEs) was similar in the younger age group (6 to 11-year-olds) and the older age group (12 to 17-year-olds). Serious adverse events occurred in six patients in the younger age group, and four patients in the older age group, who received viloxazine ER; no serious adverse events were observed in the placebo group. Patients in both age groups appeared to be equally likely to experience a TEAE leading to discontinuation, dose modification, or dose interruption. Overall, serious adverse events and dose adjustments or discontinuation because of adverse events were uncommon, but did occur more frequently in the viloxazine ER group than in the placebo group.

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Table 30. Overview of Adverse Events, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) Ages 6 to 11 Years Ages 12 to 17 Years (812P301 and 812P303) (812P302 and 812P304) Total 100 mg 200 mg 400 mg Treatment Placebo 200 mg 400 mg 600 mg Treatment Placebo Treatment Placebo N=154 N=268 N=100 N=522 N=262 N=99 N=205 N=99 N=403 N=201 N=925 N=463 Event Category1 % % % % % % % % % % % % Any TEAE 48 50 58 51 36 43 56 56 53 38 52 37 Moderate or 18 18 37 22 14 19 23 26 23 14 22 14 severe AEs SAE 1 1 2 1 0 2 1 0 1 0 1 0 SAEs with fatal 0 0 0 0 0 0 0 0 0 0 0 0 outcome AE leading to discontinuation 3 3 4 3 2 4 3 5 4 1 4 1 of study drug AE leading to dose modification of 0 1 4 1 1 3 2 0 2 2 1 1 study drug AE leading to interruption of 0 1 4 1 1 3 2 0 2 2 1 1 study drug AE leading to reduction of 0 0 0 0 0 0 0 0 0 0 0 0 study drug AE leading to delay of study 0 0 0 0 0 0 0 0 0 0 0 0 drug Source: adae.xpt. Software, Python. Table created by the Clinical Data Scientist and Clinical Review Team. 1 Treatment-emergent AEs are defined as AEs with onset or an increase in severity at any time from the first exposure to study drug. Abbreviations: AE = adverse event; SAE = severe adverse event; TEAE = treatment-emergent adverse event 7.5.2. Deaths No deaths occurred during the viloxazine extended-release development program.

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Serious Adverse Events The most common serious adverse events (SAEs) in patients receiving viloxazine ER in the phase 3 placebo-controlled trials (812P301, 812P302, 812P303, and 812P304) were suicidal ideation or behavior (3 patients) and syncope (3 patients). Half of the SAEs in the phase 3 trials were in the Psychiatric Disorders SOC (Table 31). No SAEs were reported in Study 812P202, a phase 2 dose-ranging study. In the long-term safety extension study (812P310), 25 of 1097 patients who received study medication experienced SAEs. The most common SAEs reported in Study 812P310 were suicidal ideation, syncope, and seizure (Table 32). Table 31. Serious Adverse Events, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) Ages 6 to 11 Years Ages 12 to 17 Years Total (Trials 812P301 and 812P303) (Trials 812P302 and 812P304) 100 mg 200 mg 400 mg Treatment Placebo 200 mg 400 mg 600 mg Treatment Placebo Treatment Placebo Serious Adverse N=154 N=268 N=100 N=522 N=262 N=99 N=205 N=99 N=403 N=201 N=925 N=463 Event1,2 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Any serious TEAE 2 (1) 2 (1) 2 (2.0) 6 (1) 0 2 (2) 2 (1) 0 4 (1) 0 10 (1) 0 Conduct disorder 1 (1) 0 0 1 (0.2) 0 0 0 0 0 0 1 (0.1) 0 Pyromania 1 (1) 0 0 1 (0.2) 0 0 0 0 0 0 1 (0.1) 0 Appendicitis 0 1 (0.4) 0 1 (0.2) 0 0 0 0 0 0 1 (0.1) 0 Suicidal ideation 0 1 (0.4) 0 1 (0.2) 0 0 0 0 0 0 1 (0.1) 0 Syncope 0 0 1 (1) 1 (0.2) 0 1 (1) 1 (0.5) 0 2 (0.5) 03 (0.3) 0 Suicidal behavior 0 0 1 (1) 1 (0.2) 0 0 0 0 0 0 1 (0.1) 0 Thermal burn 0 0 0 0 0 1 (1) 0 0 1 (0.2) 01 (0.1) 0 Suicide attempt 0 0 0 0 0 0 1 (0.5) 0 1 (0.2) 01 (0.1) 0 Source: adae.xpt. Software, Python. Created by the Clinical Data Scientist and Clinical Review Team. 1 Serious adverse events are defined as those AEs resulting in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 2 Terms included are those that occurred more often in the treatment than comparator group Abbreviations: N = number of subjects in the group; n = number of subjects with the adverse event; TEAE = treatment-emergent adverse event

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Table 32. Serious Adverse Events (Study 812P310) Number of % of Total Serious Adverse Event Patients (N=1097) Suicidal ideation 10 0.9% Syncope 4 0.4% Seizure (Epilepsy, Generalized tonic-clonic seizure, petit mal epilepsy) 3 0.3% Intentional self-injury 2 0.2% Major depression 2 0.2% Suicide attempt 2 0.2% Affective disorder 1 0.1% Aggression 1 0.1% Appendicitis 1 0.1% Atrial septal defect 1 0.1% Biliary colic 1 0.1% Borderline personality disorder 1 0.1% Burns second degree 1 0.1% Dyspnea 1 0.1% Hallucination, auditory 1 0.1% Humerus fracture 1 0.1% Palpitations 1 0.1% Psychotic disorder 1 0.1% Nonepileptiform seizure 1 0.1% Type 1 diabetes mellitus 1 0.1% Source: adae.xpt. Created by the Clinical Reviewer. Patients receiving viloxazine ER were more likely than patients on placebo to report suicidal ideation and behavior in the controlled phase 3 studies. Two patients reported SAEs of suicidal behaviors in the controlled studies. In addition, suicidal ideation was classified as an SAE for one patient. Suicidal ideation, self-injury, and suicide attempts were also reported as SAEs in the long-term safety extension study. Adverse events of suicidal ideation and behavior, including case narratives, are discussed in detail in Section 7.6.2. Seizures and adverse events that could represent seizure (syncope, syncopal episode, pseudoseizure, myoclonus, severe muscle spasm) were reported as adverse events of special interest in this development program. In the phase 3 short-term safety and efficacy studies, 3 viloxazine-treated patients (and no placebo-treated patients) reported syncope. In Study 812P310, four patients reported SAEs of syncope. As adverse events of special interest, these events were classified as serious, although no patients who reported syncope were hospitalized or experienced life-threatening symptoms. No other adverse events of special interest were reported in the short-term safety and efficacy studies. Three patients experienced seizures in Study 812P310. The details of these cases and the review issues relevant to the potential risk of seizures with viloxazine exposure are discussed in Section 7.6.1. The clinical narratives for the syncope events in the controlled phase 3 trials are below:  Patient 302-(b) (6) : a 13-year-old female who was randomized to receive viloxazine ER 200 mg in Study 812P302. She had a syncopal episode 23 days after first intake of study medication. The episode was accompanied by lower abdominal pain, lightheadedness, and weakness. The patient was evaluated in an emergency department, where an electrocardiogram revealed an elevated QTc interval (472 msec) and laboratory assessments showed hyponatremia (serum sodium, 132 mmol/L). The patient was given intravenous fluids and referred for cardiology evaluation. Viloxazine ER was discontinued. During the 71 Integrated Review Template, version date 2019/10/16

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cardiology evaluation, the patient’s mother reported that the patient had previously experienced similar presyncopal and syncopal episodes. Her echocardiogram and electrocardiogram were within normal limits. Holter monitoring and increased fluid and salt intake were recommended.

 Patient 303-(b) (6) : 9-year-old female who received viloxazine ER 400 mg in Study 812P303. The patient experienced a syncopal episode 17 days after first intake of study medication. The event occurred in the context of deliberate breath-holding at school; the patient reported that she was trying to turn her face red in view of her peers. No seizure-like activity occurred, and the patient immediately returned to her class activities.

 Patient 304-(b) (6) : 12-year-old female who received viloxazine ER 400 mg in Study 812P304. The patient experienced nausea and diarrhea approximately 4 days after first intake of study medication. One week later, the patient had an episode of vomiting but felt well enough to go to school. While at school that day, the patient felt dizzy and fainted after standing up. She had reportedly been engaged in physical exercise in 104°F heat. Of note, her brother had been diagnosed with a viral illness 2 weeks earlier. The patient recovered and continued study medication. The clinical narratives for the syncope events in Study 812P310 are below:  Patient 304-(b) (6) : 16-year-old female who received placebo in Study 812P304. Approximately 4 months after starting study medication, she reportedly had a syncopal episode with subsequent seizure-like activity versus myoclonus. Her mother reported that she was overheated after being outside, felt dizzy, fell, hit her head, and passed out while in a hot laundry room. The patient was evaluated at a hospital and discharged. The Principal Investigator assessed the clinical history to be inconsistent with a seizure occurring before or after the fall.

 Patient 302-(b) (6) : 16-year-old female who was randomized to receive placebo in Study 812P302. She experienced an SAE of syncope approximately 4 months after enrollment in Study 812P310. Of note, this patient also experienced a suspected generalized tonic-clonic seizure while enrolled in 812P310. Additional details from the clinical narrative can be found in Section 7.6.1.

 Patient 304-(b) (6) : 15-year-old male who received viloxazine ER 400 mg in Study 812P304. His medical history was remarkable for hypertension, episodes of dizziness upon standing, and a history of syncope while enrolled in a clinical trial for an antihypertensive medication. Eighty days after he began receiving study medication, he had a syncopal episode when moving from sitting to standing position. The episode lasted <1 minute. The patient recovered and the dose was unchanged.

 Patient 301-(b) (6) : 10-year-old male who received viloxazine ER 200 mg in Study 812P301. Eighty-one days after exposure to study medication, his father reported that the patient had experienced cough, chest pain, and syncope. No details regarding the duration or quality of the symptoms were provided. A chest x-ray and electrocardiogram were within normal limits. The patient was evaluated and diagnosed with conversion disorder. Two

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Table 33. Adverse Events Leading to Discontinuation, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) Ages 6 to 11 years Ages 12 to 17 Years (812P301 and 812P303) (812P302 and 812P304) Total 100 mg 200 mg 400 mg Treatment Placebo 200 mg 400 mg 600 mg Treatment Placebo Treatment Placebo N=154 N=268 N=100 N=522 N=262 N=99 N=205 N=99 N=403 N=201 N=925 N=463 Adverse Event1,2 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Treatment discontinuation due to 5 (3) 8 (3) 4 (4) 17 (3) 5 (1.9) 4 (4) 6 (3) 5 (5) 15 (4) 1 (1) 32 (4) 6 (1) TEAEs Somnolence 0 2 (1) 02 (0.4) 01 (1) 2 (1) 2 (2) 5 (1) 07 (1) 0 Fatigue 1 (1) 1 (0.4) 02 (0.4) 0 0 0 1 (1) 1 (0.2) 03 (0.3) 0 Nausea 0 2 (1) 02 (0.4) 001 (1) 0 1 (0.2) 03 (0.3) 0 Tachycardia 1 (1) 1 (0.4) 02 (0.4) 0 0 0 1 (1) 1 (0.2) 03 (0.3) 0 Decreased appetite 0 2 (1) 02 (0.4) 000 00 02 (0.2) 0 Irritability 0 2 (1) 02 (0.4) 000 00 02 (0.2) 0 Headache 0 1 (0.4) 01 (0.2) 001 (1) 0 1 (0.2) 02 (0.2) 0 Aggression 1 (1) 0 0 1 (0.2) 2 (1) 00 0 0 01 (0.1) 2 (0.4) Conduct disorder 1 (1) 0 0 1 (0.2) 00 0 0 01 (0.1) 0 Dizziness 1 (1) 0 0 1 (0.2) 000 00 01 (0.1) 0 Electrocardiogram 1 (1) 0 0 1 (0.2) 0 0 0 0 0 0 1 (0.1) 0 t-wave inversion Pyromania 1 (1) 0 0 1 (0.2) 000 00 01 (0.1) 0 Affect lability 0 1 (0.4) 01 (0.2) 1 (0.4) 00 0 0 01 (0.1) 1 (0.2) Abdominal discomfort 0 1 (0.4) 01 (0.2) 000 00 01 (0.1) 0 Erection increased 0 1 (0.4) 01 (0.2) 000 00 01 (0.1) 0 Hot flush 0 1 (0.4) 01 (0.2) 000 00 01 (0.1) 0 Hyperacusis 0 1 (0.4) 01 (0.2) 000 00 01 (0.1) 0 Impulsive behavior 0 1 (0.4) 01 (0.2) 000 00 01 (0.1) 0 Insomnia 0 1 (0.4) 01 (0.2) 000 00 01 (0.1) 0 Mood swings 0 1 (0.4) 01 (0.2) 000 00 01 (0.1) 0 Sleep terror 0 1 (0.4) 01 (0.2) 000 00 01 (0.1) 0 Flat affect 0 0 1 (1) 1 (0.2) 000 00 01 (0.1) 0 Gastroenteritis 0 0 1 (1) 1 (0.2) 000 00 01 (0.1) 0 Mood altered 0 0 1 (1) 1 (0.2) 000 00 01 (0.1) 0 Sedation 0 0 1 (1) 1 (0.2) 000 00 01 (0.1) 0 Abdominal pain 0 0 0 0 0 1 (1) 0 0 1 (0.2) 01 (0.1) 0 Anxiety 0 0 00 01 (1) 0 0 1 (0.2) 01 (0.1) 0 Diarrhea 0 0 0 0 0 1 (1) 0 0 1 (0.2) 01 (0.1) 0

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Ages 6 to 11 years Ages 12 to 17 Years (812P301 and 812P303) (812P302 and 812P304) Total 100 mg 200 mg 400 mg Treatment Placebo 200 mg 400 mg 600 mg Treatment Placebo Treatment Placebo N=154 N=268 N=100 N=522 N=262 N=99 N=205 N=99 N=403 N=201 N=925 N=463 Adverse Event1,2 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Syncope 0 0 0 0 0 1 (1) 0 0 1 (0.2) 01 (0.1) 0 Abdominal pain upper 0 0 0 0 0 0 1 (1) 0 1 (0.2) 01 (0.1) 0 Suicide attempt 0 0 0 0 0 0 1 (1) 0 1 (0.2) 01 (0.1) 0 Terminal insomnia 0 0 0 0 0 0 1 (1) 0 1 (0.2) 01 (0.1) 0 Vomiting 0 0 00 0 01 (1) 0 1 (0.2) 01 (0.1) 0 Depressed mood 0 0 0 0 0 0 0 1 (1) 1 (0.2) 01 (0.1) 0 Dizziness postural 0 0 0 0 0 0 0 1 (1) 1 (0.2) 01 (0.1) 0 Vitiligo 0 0 0 0 0 0 0 1 (1) 1 (0.2) 01 (0.1) 0 Suicidal ideation 0 0 0 0 0 0 0 0 0 1 (0.5) 01 (0.2) Agitation 0 0 0 0 1 (0.4) 00 0 0 0 01 (0.2) Tic 0 0 0 0 1 (0.4) 00 0 0 0 01 (0.2) Source: adae.xpt; Software, Python. Table created by the Clinical Data Scientist and Clinical Review Team. 1 Treatment-emergent adverse events, defined as those AEs with onset or increase in severity at any time from the first exposure to study drug. Terms included are those that occurred more often in the treatment than comparator group. 2 Coded as MedDRA preferred terms Abbreviations: AE = adverse event; N = number of subjects in treatment arm; n = number of subjects with the adverse event; TEAE = treatment-emergent adverse event Table 34. FDA MedDRA Queries (Narrow) Leading to Discontinuation, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) Ages 6 to 11 Years Ages 12 to 17 Years (812P301 and 812P303) (812P302 and 812P304) Total 100 mg 200 mg 400 mg Treatment Placebo 200 mg 400 mg 600 mg Treatment Placebo Treatment Placebo FDA MedDRA N=154 N=268 N=100 N=522 N=262 N=99 N=205 N=99 N=403 N=201 N=925 N=463 Query1 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Somnolence 0 2 (1) 1 (1) 3 (1) 0 1 (1) 2 (1) 2 (2) 5 (1) 0 8 (1) 0 Somnolence 0 2 (1) 0 2 (0.4) 0 1 (1) 2 (1) 2 (2) 5 (1) 0 7 (1) 0 Sedation 0 0 1 (1) 1 (0.2) 0 0 0 0 0 0 1 (0.1) 0

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Ages 6 to 11 Years Ages 12 to 17 Years (812P301 and 812P303) (812P302 and 812P304) Total 100 mg 200 mg 400 mg Treatment Placebo 200 mg 400 mg 600 mg Treatment Placebo Treatment Placebo FDA MedDRA N=154 N=268 N=100 N=522 N=262 N=99 N=205 N=99 N=403 N=201 N=925 N=463 Query1 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Abdominal pain 0 1 (0.4) 0 1 (0.2) 0 1 (1) 1 (1) 0 2 (1) 0 3 (0.3) 0 Abdominal 0 1 (0.4) 0 1 (0.2) 0 0 0 0 0 0 1 (0.1) 0 discomfort Abdominal 0 0 0 0 0 1 (1) 0 0 1 (0.2) 0 1 (0.1) 0 pain Abdominal 0 0 0 0 0 0 1 (1) 0 1 (0.2) 0 1 (0.1) 0 pain upper Fatigue 1 (1) 1 (0.4) 0 2 (0.4) 0 0 0 1 (1) 1 (0.2) 0 3 (0.3) 0 Nausea 0 2 (1) 0 2 (0.4) 0 0 1 (1) 0 1 (0.2) 0 3 (0.3) 0 Tachycardia 1 (1) 1 (0.4) 0 2 (0.4) 0 0 0 1 (1) 1 (0.2) 0 3 (0.3) 0 Decreased 0 2 (1) 0 2 (0.4) 0 0 0 0 0 0 2 (0.2) 0 appetite Dizziness 1 (1) 0 0 1 (0.2) 0 0 0 1 (1) 1 (0.2) 0 2 (0.2) 0 Dizziness 0 0 0 0 0 0 0 1 (1) 1 (0.2) 0 1 (0.1) 0 postural Dizziness 1 (1) 0 0 1 (0.2) 0 0 0 0 0 0 1 (0.1) 0 Headache 0 1 (0.4) 0 1 (0.2) 0 0 1 (1) 0 1 (0.2) 0 2 (0.2) 0 Insomnia 0 1 (0.4) 0 1 (0.2) 0 0 1 (1) 0 1 (0.2) 0 2 (0.2) 0 Terminal 0 0 0 0 0 0 1 (1) 0 1 (0.2) 0 1 (0.1) 0 insomnia Insomnia 0 1 (0.4) 0 1 (0.2) 0 0 0 0 0 0 1 (0.1) 0

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Ages 6 to 11 Years Ages 12 to 17 Years (812P301 and 812P303) (812P302 and 812P304) Total 100 mg 200 mg 400 mg Treatment Placebo 200 mg 400 mg 600 mg Treatment Placebo Treatment Placebo FDA MedDRA N=154 N=268 N=100 N=522 N=262 N=99 N=205 N=99 N=403 N=201 N=925 N=463 Query1 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Irritability 0 2 (1) 0 2 (0.4) 1 (0.4) 0 0 0 0 0 2 (0.2) 1 (0.2) Irritability 0 2 (1) 0 2 (0.4) 0 0 0 0 0 0 2 (0.2) 0 Agitation 0 0 0 0 1 (0.4) 0 0 0 0 0 0 1 (0.2) Anxiety 0 0 0 0 0 1 (1) 0 0 1 (0.2) 0 1 (0.1) 0 Depression 0 0 0 0 0 0 0 1 (1) 1 (0.2) 0 1 (0.1) 0 Depressed 0 0 0 0 0 0 0 1 (1) 1 (0.2) 0 1 (0.1) 0 mood Diarrhea 0 0 0 0 0 1 (1) 0 0 1 (0.2) 0 1 (0.1) 0 Dyspepsia 0 0 0 0 0 0 1 (1) 0 1 (0.2) 0 1 (0.1) 0 Abdominal 0 0 0 0 0 0 1 (1) 0 1 (0.2) 0 1 (0.1) 0 pain upper Parasomnia 0 1 (0.4) 0 1 (0.2) 0 0 0 0 0 0 1 (0.1) 0 Sleep terror 0 1 (0.4) 0 1 (0.2) 0 0 0 0 0 0 1 (0.1) 0 Self-harm 0 0 0 0 0 0 1 (1) 0 1 (0.2) 0 1 (0.1) 0 Suicide 0 0 0 0 0 0 1 (1) 0 1 (0.2) 0 1 (0.1) 0 attempt Syncope 0 0 0 0 0 1 (1) 0 0 1 (0.2) 0 1 (0.1) 0 Vomiting 0 0 0 0 0 0 1 (1) 0 1 (0.2) 0 1 (0.1) 0 Source: adae.xpt. Software, Python. Created by the Clinical Data Scientist and Clinical Review Team 1 Terms included are those that occurred more often in the treatment than the comparator group. Abbreviations: MedDRA = Medical Dictionary of Regulatory Activities; N = number of subjects in the treatment arm; n = number of subjects with the adverse event

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The phase 2 safety and efficacy study (812P202) included 193 patients exposed to viloxazine (doses ranging from 100 mg to 400 mg). No patient in the placebo group experienced adverse events that led to discontinuation. The adverse events that most commonly led to discontinuation in the viloxazine ER treatment groups were headache (4 patients) and irritability (2 patients). In Study 812P310, the adverse events that most frequently led to discontinuation were somnolence, suicidal ideation, fatigue, decreased appetite, and headache. See Appendix 17 for a description of additional safety findings from Studies 812P202 and 812P310. 7.5.4. Treatment-Emergent Adverse Events Table 35 provides an overview of the treatment-emergent adverse events (TEAEs) that occurred in ≥2% of patients in the viloxazine ER treatment groups and occurred more frequently than in the placebo groups. The most common TEAEs were somnolence/sedation, headache, fatigue, decreased appetite, abdominal pain, upper respiratory infection, nausea, and vomiting. Somnolence was the most commonly reported preferred term in the phase 3 placebo-controlled trials (13% of viloxazine-treated patients vs. 3.5% of placebo-treated patients, Table 35). In these studies, somnolence was the most commonly-reported TEAE in all age and dose groups and was the TEAE that most commonly led to discontinuation. Somnolence appeared to be dose related, occurring in 19% of patients in the 600 mg treatment group, 14% of patients in the 400 mg group, 12% of patients in the 200 mg group, and 10% of patients in the 100 mg group. Sedation was also reported more frequently in viloxazine ER–treated patients (3.5%) than placebo-treated patients (0.4%). The FDA MedDRA Query (FMQ) of somnolence includes the preferred terms of somnolence, sedation, and lethargy. In the phase 3 trials, one of these three terms was reported in 16.9% of patients who were exposed to viloxazine ER and 0.9% of patients receiving placebo (Table 36). Somnolence was reported in 21.2% of viloxazine-treated patients in Study 812P202, compared with 4.2% of placebo-treated patients. Sedation was reported in 2.1% of viloxazine ER patients and no placebo-treated patients. The Applicant’s draft labeling includes a warning about (b) (4) , and advises to use caution when driving or operating (b) (4) machinery, though no formal driving study was conducted.

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Table 35. Adverse Events1 Occurring at ≥2% and at a Higher Frequency in the Treatment Arm than the Comparator Arm, Phase 3 Safety Population Patients Aged 6 to 11 Years Patients Aged 12 to 17 Years (812P301 and 812P303) (812P302 and 812P304) Total 100 mg 200 mg 400 mg Treatment Placebo 200 mg 400 mg 600 mg Treatment PlaceboTreatment Placebo Adverse N=154 N=268 N=100 N=522 N=262 N=99 N=205 N=99 N=403 N=201 N=925 N=463 Event1,2 % % % % % % % % % % % % 48 50 58 51 36 43 56 56 53 38 52 37 Any TEAE 10 12 14 12 2 13 14 19 15 6 13 4 Somnolence 10 11 6 10 4 10 13 9 11 10 10 7 Headache Decreased 5 9 9 8 0 5 7 6 7 1 7 0.4 appetite 4 6 9 6 2 4 9 10 8 3 7 2 Fatigue 1 3 2 3 2 7 9 9 8 4 5 3 Nausea 5 3 7 4 2 2 5 4 4 2 4 2 Vomiting 3 5 6 5 4 2 4 4 4 4 4 4 Nasopharyngitis Abdominal pain 3 4 6 4 2 3 3 4 4 3 4 2 upper 2 4 3 3 0 2 5 4 4 1 4 0.4 Sedation 3 2 6 3 2 3 4 5 4 1 4 1 Irritability 1 3 3 3 1 1 2 4 2 0 2 0.4 Insomnia Source: adae.xpt; Software, Python; modified by Clinical Review Team 1 Treatment-emergent adverse events are defined as AEs with onset or an increase in severity at any time from the first exposure to study drug. 2 Coded as MedDRA preferred terms Abbreviations: N = number of subjects in the treatment arm; n = number of subjects with the adverse event; TEAE = treatment-emergent adverse event

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Table 36. FDA MedDRA Queries1 Occurring at ≥2% and at a Higher Frequency in the Treatment Arm than the Comparator Arm, Phase 3 Safety Population Patients Aged 6 to 11 Years Patients Aged 12 to 17 Years (812P301 and 812P303) (812P302 and 812P304) Total 100 mg 200 mg 400 mg Treatment Placebo 200 mg 400 mg 600 mg Treatment Placebo Treatment Placebo FDA MedDRA N=154 N=268 N=100 N=522 N=262 N=99 N=205 N=99 N=403 N=201 N=925 N=463 Query1,2 % % % % % % % % % % % % Somnolence 12 16 18 15 2 15 19 23 19 7 17 4 (narrow FMQ) Headache 10 11 7 10 5 10 14 9 12 10 11 7 (narrow FMQ) Fatigue (narrow 4 6 11 7 2 5 9 10 8 3 7 2 FMQ) Decreased appetite 5 9 9 8 0 5 7 6 7 1 7 0.4 (narrow FMQ) Abdominal pain 3 6 11 6 5 6 4 6 5 3 6 4 (narrow FMQ) Nasopharyngitis 4 7 9 7 6 2 5 5 4 4 6 5 (narrow FMQ) Nausea (narrow 1 3 2 3 2 7 9 9 8 4 5 3 FMQ) Vomiting (narrow 5 3 7 4 2 2 5 4 4 2 4 2 FMQ) Insomnia (narrow 2 6 7 5 2 2 3 4 3 1 4 1 FMQ) Dyspepsia 3 4 6 4 2 3 3 5 4 3 4 3 (narrow FMQ) Irritability (narrow 3 2 6 3 3 3 4 5 4 1 4 2 FMQ) Source: adae.xpt; Software: Python. Created by the Clinical Data Scientist and Clinical Review Team. 1 Treatment-emergent adverse event defined as those AEs with onset or increase in severity at any time from the first exposure to study drug. 2 Coded as MedDRA preferred terms Abbreviations: AE = adverse event; FMQ = FDA MedDRA Query; MedDRA = Medical Dictionary of Regulatory Activities; N = number of subjects in treatment arm; n = number of subjects with adverse event

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Somnolence and sedation were frequently observed in clinical trials of other nonstimulant treatments for ADHD. Somnolence or sedation was reported in 11% of atomoxetine-treated patients and 4% of placebo-treated patients in child and adolescent studies. Somnolence was also one of the most common reasons for atomoxetine treatment discontinuation. No warning for somnolence or sedation is included in the atomoxetine labeling. In two fixed-dose studies that compared guanfacine ER to placebo, 38% of patients treated with guanfacine ER reported somnolence (including somnolence, sedation, and hypersomnia), compared with 11% of patients receiving placebo. Greater than 30% of patients treated with clonidine ER in fixed-dose studies reported somnolence or sedation, compared with 4% of placebo-treated patients. The approved labeling for guanfacine ER and clonidine ER contains a warning for somnolence/sedation. Patients are cautioned against operating heavy machinery or driving until they know how these medications will affect them. Healthcare professionals are advised to consider the potential of additive sedative effects and counsel patients to avoid use of alcohol. Reviewer’s note: Somnolence and sedation were commonly reported in patients receiving viloxazine ER. The functional impacts of these effects were not specifically studied, but they could potentially have clinically meaningful repercussions in a pediatric population (e.g., effects on school and social functioning and risks of falls and accidents). Somnolence and sedation were also relatively common in the atomoxetine program, suggesting the possibility of a class effect, although the atomoxetine labeling does not include this warning. Given how frequently somnolence and sedation occurred (almost 17% of patients receiving viloxazine ER), the apparent correlation with dose, and the potential clinical implications, the risk of somnolence and sedation should be described in Section 6 of the labeling. The potential risk of driving or operating (b) (4) machinery while receiving viloxazine ER treatment is appropriate for inclusion in Section 5 (Warnings and Precautions). Of note, higher rates of somnolence and sedation were reported in clinical trials of alpha agonists, which carry a related warning. However, no study directly compared these other drugs to viloxazine ER, so no firm conclusions about the relative frequency of somnolence and sedation in patients taking alpha agonists versus viloxazine ER can be made. Decreased appetite was also reported more frequently in patients receiving viloxazine ER than in those receiving placebo. The review team evaluated data related to the short- and long-term effects of viloxazine ER on appetite and growth parameters. See Section 7.6.3 for a full discussion of this risk issue. 7.5.5. Laboratory Findings No clinically meaningful differences in mean laboratory values were observed in viloxazine ER- treated patients, as compared to patients on placebo. Most laboratory values in the phase 3 controlled studies remained within the reference ranges for age. Patients receiving viloxazine ER were more likely than those on placebo to experience a shift in liver transaminases from within the normal ranges to above the upper limit of the reference ranges (Table 37). See Section 7.6.5 for a full discussion of the effect of viloxazine ER on hepatobiliary assessments. Otherwise, the frequency of out-of-range laboratory values at EOS or early termination visits was comparable in the viloxazine ER and placebo groups. See Appendix 17, Clinical Safety Assessment: Additional Information and Assessment, for details of laboratory findings in the clinical trials.

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Table 37. Liver Transaminases, Shifts from Normal to Elevated at End of Study Visit, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) Viloxazine ER Placebo n (%) n (%) Alanine aminotransferase N=816 N=421 >ULN 47 (6) 8 (2) >2-fold ULN 6 (1) 0 Lab analysis B N=817 N=423 >ULN 20 (2) 3 (1) >2-fold ULN 2 (0.2) 0 Source: ad b.xpt. Includes end-of-study and early termination visits; modified by Clinical Review Team. Abbreviations: ER = extended release; N = number of subjects; n = number of subjects with abnormality; ULN = upper limit of normal 7.6. Key Review Issues Relevant to the Evaluation of Risk 7.6.1. Risk of Seizure

Issue

Viloxazine caused seizures/convulsions in multiple animal species (rat, dog, and mouse) at therapeutically relevant doses, suggesting a potential risk for seizures with chronic use of viloxazine.

Background

In nonclinical safety studies, viloxazine, likely due to its adrenergic pharmacology, caused convulsions in multiple animal species at therapeutically relevant doses. Specifically, viloxazine caused convulsions at ≥130 mg/kg/day in rat, ≥173 mg/kg/day in mouse, and ≥39 mg/kg/day in dog, which are approximately 1.5-, 1-, and 1.5-fold the MRHD of 400 mg, based on mg/m2 in children2, respectively. More importantly, the threshold for convulsions decreased with repeat viloxazine treatment (Table 38). It should be noted that the decrease in the convulsion threshold was not due to drug accumulation because no significant changes in drug exposure were observed after repeat treatment. Table 38. Summary of Viloxazine-Related Convulsion and CNS Findings in Nonclinical Studies Safety Marginb a 2 Study and Duration Dose Convulsion-Related Findings mg/m Cmax Human, MRHD 400 mg, Cmax: 3.9 µg/mL; AUC: 61.2 µg*hour/mL (from Studies 812P301 and 303 in children aged 6 to 11 years) Rat Single dose ≥487 Ataxia, convulsions, and death 6x NA 7-day ≥433 Ataxia, tremors, convulsions, and deaths 5x 2–3× 2-yearc ≥130 Ataxia, tremors, and convulsions 1.5× NA

2 Because the proposed indication is for the pediatric population only (patients with ADHD ages 6 to 17 years), body surface area (mg/m2)-based safety margins are calculated using the average child body weight of 20 kg and conversion factor Km of 25.

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Safety Marginb a 2 Study and Duration Dose Convulsion-Related Findings mg/m Cmax Dog 7-day 87 Ataxia and convulsion, leading to early termination 3.5× 4× 13-week 39 Impaired muscle coordination, tremors, and 1.5× 2× convulsions Mouse Single dose 434 Ataxia, convulsions, and death 2.5× NA 5-day ≥217 Recumbency and convulsions 1.5× NA 4-week 173 Convulsions 1× 2× Source: Modified/reformatted based on the data in the Applicant’s study reports a mg/kg (single dose) or mg/kg/day (multi-dose) b Exposure-based safety margins are calculated relative to the human Cmax at the MRHD of 400 mg/day because convulsions are 2 Cmax related; mg/m -based safety margins calculated using an average child body weight of 20 kg and conversion factor Km of 25 c Two-year rat carcinogenicity study; Abbreviations: AUC = area under the curve; CNS = central nervous system; MRHD = maximum recommended human dose; NA = exposure data not available

The convulsion findings across multiple nonclinical species raise concerns for the potential seizure liability for long-term or chronic use of viloxazine. The Applicant argues that the convulsion findings in nonclinical studies have limited clinical relevance in that 1) the convulsions are likely due to animal-specific and CNS-active metabolite(s); 2) the convulsions are due to a kindling effect and have limited human relevance; and 3) there are no overt brain lesions in the animals that had convulsions. In addition, the Applicant argues that existing human experience from the clinical program under this application and from previous experience in Europe did not show an increased incidence of seizures or convulsions. However, from a nonclinical perspective, the Applicant’s arguments are not adequate for the following reasons:  The Applicant has not identified the “presumed” animal-specific metabolite(s) present in all 3 nonclinical species and cause convulsions.

 Although kindling is often used as a model of epileptogenesis in nonclinical studies, it is not unique to animals. In fact, kindling has been observed in human; for example, in alcohol withdrawal leading to an increased risk (i.e., lower threshold) of seizures (Becker 1998).

 Lack of histopathology findings in the brain does not exclude the possibility of moderate and/or functional impairment associated with seizures/convulsions. Although seizures were observed in nonclinical studies, no seizures or convulsions were reported in the controlled phase 2 or phase 3 clinical trials. The Division has previously expressed concern to the Applicant that a seizure risk may become more evident with long-term use. Seizures were reported in the long-term safety extension study. The assessment of this review issue focused on characterizing the clinical significance of the findings in the nonclinical studies and the long-term clinical study. Of note, the long-term safety extension was uncontrolled and cannot provide information on the relative risk of seizure with viloxazine ER exposure compared to the background risk in the population. However, the clinical data were examined for any indicators of an association between viloxazine ER and the seizure events. The review also considered published literature and available European postmarketing data from use of immediate-release viloxazine as an antidepressant.

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Assessment

The population of patients enrolled in viloxazine ER clinical trials likely had a low baseline risk of seizure. The protocols for the phase 2 and 3 studies specifically excluded patients with seizures or a history of seizure disorder within the immediate family (siblings, parents), or a history of seizure-like events. Among the patients who enrolled in the studies, 8 had a reported history of febrile seizures and 1 had a history of “infantile seizures”; no other seizure disorders were reported. Patients with significant systemic disease or major neurologic disorders—which could theoretically increase the seizure risk—were also excluded. The submitted data therefore do not provide any information on the risk of viloxazine ER in patients who may be at higher risk for seizures. Seizures and adverse events that may represent seizure (syncope, syncopal episode, pseudoseizure, myoclonus, and severe muscle spasm) were tracked as adverse events of special interest. No seizures were reported in the controlled phase 2 and phase 3 studies (812P202, 812P301, 812P302, 812P303, and 812P304). Syncope was reported in three patients in the phase 2 and phase 3 controlled studies. No patient in the placebo group reported syncope. No other adverse events of special interest were reported in the controlled studies. Three patients experienced seizures during the open-label safety extension study (812P310):  Patient 302-(b) (6) : 16-year-old female who experienced a tonic-clonic seizure 5 months after starting open-label viloxazine treatment. The patient had received placebo during the double-blind treatment period. The patient’s dosage was titrated to viloxazine ER 600 mg during the open-label extension. The patient also experienced a syncopal episode approximately 4 months after entering the open-label study. The seizure episode was characterized by jerking movements and tongue biting. No bowel or bladder incontinence was reported. The episode lasted approximately 1 minute and was followed by a 10-minute postictal period. The patient was evaluated in an emergency department and diagnosed with a tonic-clonic seizure. The patient was prescribed diazepam, referred to neurology, and discharged home. Awake and asleep EEGs performed 10 days later were reportedly normal. The patient was evaluated by a neurologist who considered possible diagnoses of syncope or epileptic seizure. Magnetic resonance imaging (MRI) was recommended but the results are not available in the case narrative.

 Patient 202-(b) (6) : 8-year-old female with a history of muscle spasms who had a generalized tonic-clonic seizure 19 days after starting open-label viloxazine. The patient had received viloxazine ER 100 mg during the double-blind treatment period and the patient’s dose of viloxazine was titrated to 300 mg in the open-label period. The episode was characterized by leg cramping, lower extremity tingling, screaming, kicking, rhythmic movements of the upper extremities, eye rolling, and jaw clenching. The episode lasted 45 to 90 sec and was followed by a postictal period. The patient did not have associated fever, traumatic injury, or stressors. The patient was evaluated by a neurologist approximately 1 week later and was diagnosed with benign rolandic epilepsy. Awake and asleep EEGs were reportedly normal. The patient had additional seizure episodes >30 days after study drug discontinuation and was started on levetiracetam. An MRI revealed scattered T2 hyperintensities.

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 Patient 303-(b) (6) : 11-year-old female who reported episodes of staring and distractibility approximately one year after starting open-label treatment with viloxazine. The patient received viloxazine ER 200 mg in the double-blind study. In the open-label study, her dose was titrated to 600 mg, then decreased to 400 mg because of lack of improvement on the higher dose. An EEG was performed and reported to be consistent with absence seizures. The patient was started on treatment with ethosuximide. The parent reported that similar episodes may have occurred as early as (b) (6) A follow-up safety report provided an updated EEG result and indicated that no seizures were observed but that the EEG did reveal atypical spike and slow wave complexes suggestive of underlying seizure tendency. No clear association between viloxazine ER and these seizure events can be deduced from the case narratives. The development of seizure in a 16-year-old female (302-(b) (6) ) with no history of epilepsy is most suspicious for a drug-associated adverse event. However, the results of toxicology screening, other laboratory studies, and the recommended MRI were not provided, and so other contributory causes cannot be ruled out based on the available information. The neurologist who evaluated this patient was also reportedly considering nonepileptic etiologies (e.g., syncope) as an explanation for the patient’s symptoms. The clinical history described for patient 202(b) (6) is plausibly consistent with benign rolandic epilepsy. In addition, this patient continued to have seizures even after the drug was withdrawn, making an association with the drug less likely. Finally, the symptoms that prompted the seizure evaluation for patient 303-(b) (6) may have preceded exposure to viloxazine ER. One 7-year-old male patient (301-1(b) (6) ) experienced a nonepileptiform seizure while enrolled in Study 812P310. Approximately 9 months after starting study medication, the patient exhibited whole-body shaking with his eyes closed. He immediately returned to his neurologic baseline. The event was witnessed by an emergency department physician. A computed tomography scan of the head was within normal limits. The patient was discharged from the emergency room. He had another event in the parking lot. Emergency Medical Services responded and indicated he was “faking” the events. The patient and his mother ultimately reported significant psychosocial strain, including parental conflict and an open child-abuse case. Viloxazine ER was stopped for 3 days. The patient did not have any further events after resuming the medication. The investigator assessed the event as unrelated to study medication. Based on the information available in the narrative, the categorization of the event as a nonepileptiform seizure appears reasonable. The patient did not appear to have movements typical of a generalized tonic clonic or focal seizure, he did not have postictal symptoms, he was experiencing psychosocial stressors that could increase the risk for conversion reactions, and he did not have any further events while still receiving the medication. In Study 812P310, one patient (304- (b) (6) ) experienced “seizure-like activity versus myoclonus” in the context of a syncopal episode. Another patient (302-(b) (6) ) experienced a syncopal episode approximately 2 months prior to having a generalized seizure, though it is not clear that the syncopal episode and the seizure were related. See Section 7.5.4 for a discussion of these case narratives and other syncope events. The available clinical information does not support reclassification of these events as seizure events rather than syncopal events, although the possibility of seizure cannot be entirely excluded. Viloxazine was previously authorized for treatment of depression in the EU. A review of the line listings of suspected adverse drug reactions in the publicly available EudraVigilance database

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(accessed February 10, 2020) found two reported cases of seizure. The World Health Organization’s Vigibase database includes 31 reports of seizure events (seizure, generalized tonic clonic seizure, petit mal epilepsy, epilepsy). No additional clinical details about the EudraVigilance or Vigibase case reports were available. A review of the FAERS database identified the following 3 reported cases of seizure or possible seizure:  3003270: 63-year-old female who was admitted to a psychiatric unit where treatment with , viloxazine, and clozepate was initiated. The patient experienced malaise with loss of consciousness. According to the report, “the hypothesis of convulsion was not dismissed.” The patient’s clinical presentation was remarkable for a serum sodium of 113 meq/L, worsening of renal insufficiency, and bacteremia with Escherichia coli. The patient recovered with antibiotic therapy, fluid restriction, and sodium supplementation.

 3231774: 82-year-old male with a history of myocardial infarction and stroke who was started on labetalol, zopiclone, viloxazine, and paracetamol and subsequently developed tonic-clonic convulsions. The patient was also prescribed spironolactone. All drugs were withdrawn 1 day after the event. The patient’s conditioned worsened and he died. The safety report indicates that the cause of death was unstated but that the following causes were considered: new stroke, epilepsy, cerebral metastases, or any of the drugs listed in the report.

 5959260: 76-year-old male with a history of heart failure, abdominal aortic aneurysm, renal failure, hypertension, and tobacco use who was hospitalized for status epilepticus. The patient was prescribed , clonazepam, viloxazine, bisoprolol, dutasteride, acetylsalicylate , tamsulosin hydrochloride, fluconazole, darbepoetin alfa, lactulose, furosemide, zopiclone, allopurinol, and simvastatin. The patient’s serum sodium was 124 meq/L and a “tendency to water abuse was observed.” All suspect drugs were discontinued. The patient recovered. The Applicant has referenced a published review of seizure incidence with viloxazine (Edwards and Glen-Bott 1984) that found that the incidence of seizures associated with viloxazine treatment in nonepileptic populations was 1/7635 (0.01%). No other systematic reviews or clinical studies examining seizure incidence in viloxazine have been published. The yearly incidence of epilepsy in the general population is approximately 48 per 100,000 people or 0.04% (Medicine 2012). The prevalence of epilepsy in the U.S. population is approximately 1.2% (Zack and Kobau 2017). The European labeling for immediate-release viloxazine includes the following warning: Convulsive events have been reported in patients that are treated for epilepsy or have a prior history of this condition or even outside the context of epilepsy. In addition, viloxazine enters into competition with certain anticonvulsive medications (, ) by inhibiting their hepatic metabolism, which leads to symptoms of overdose. Taking into account the epileptogenic potential of viloxazine, the classic precaution for use consists of reducing the dosage of the anticonvulsive, which requires close medical supervision. The data from EudraVigilance and Vigibase are difficult to interpret given that the total number of patients exposed is unknown and the true incidence of these events among patients exposed to viloxazine is unclear. In addition, these databases may contain duplicate reports. Finally, the lack 86 Integrated Review Template, version date 2019/10/16

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of clinical details accompanying the case reports precluded analysis of any confounding factors. Of note, the case reports of seizure events listed in FAERS all appear to be confounded by the presence of other medications and medical illnesses and do not clearly demonstrate an association between these events and viloxazine.

Conclusion

Viloxazine, likely due to its adrenergic pharmacology, caused convulsions across multiple nonclinical species in multiple studies, and the threshold for convulsion decreased with repeat treatment. Although nonclinical studies suggest that viloxazine may have epileptogenic potential, few seizures have been reported in clinical trials. The seizures reported in the long-term clinical trial were not clearly associated with viloxazine ER. Immediate-release viloxazine was authorized for the treatment of depression in the EU from 1976 to 2008, but the limited data from published literature and the postmarketing databases regarding the spontaneous reports of seizures in patients taking viloxazine are insufficient to determine whether seizure events were related to drug effects. The findings from the nonclinical studies should be described in the labeling. Healthcare professionals should be aware that viloxazine has not been studied in patients at high risk of seizure. Reports of seizures should continue to be monitored in the postmarketing period given the nonclinical findings. 7.6.2. Risk of Suicidal Ideation and Behavior

Issue

Patients who received viloxazine ER were more likely than patients who received placebo to experience suicidal ideation and behavior.

Background

Children and adolescents with ADHD may be more likely to experience suicidal ideation and behavior than the general pediatric population. Any increased risk of suicidal ideation and behavior associated with viloxazine ER should be characterized and described in the labeling to allow healthcare professionals to assess the benefit-risk profile. The review team evaluated the data related to suicidal ideation and behavior from the controlled clinical studies and the open- label long-term safety extension.

Assessment

In Studies 812P202, 812P301, 812P302, 812P303, and 812P304, six viloxazine ER-treated patients and two placebo-treated patients reported suicidal ideation as adverse events. All patients who experienced suicidal ideation recovered and all suicidal ideation events in the viloxazine ER group were categorized as mild. One patient (who received the 100 mg dose) was withdrawn from the study because of suicidal ideation. This patient (202-(b) (6) ) had a history of a mood disorder. No other patients who reported suicidal ideation had a reported history of a mood disorder and none reported suicidal ideation or behavior on the C-SSRS at screening or at baseline. Most of these patients did not report any other psychiatric adverse events during the study. Patients did report suicidal ideation on postbaseline C-SSRS assessments. Of note, all of

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the viloxazine ER-exposed patients who experienced suicidal ideation were male and ≤10 years of age (Table 39). Suicidal ideation in one patient (303-(b) (6) ) was categorized as a serious adverse event. The patient was a 6-year-old male who was randomized to receive viloxazine ER 200 mg. He experienced suicidal ideation 10 days after starting the drug. His mother reported that he was hyperactive and defiant but that his mood appeared to be at baseline. He was reprimanded for talking back to his mother and said, “I want to die.” He was easily distracted and calmed within 2 minutes. He did not attempt to harm himself. He did not have a history of suicidal ideation. Although suicidal ideation was categorized as a serious adverse event, the patient was not hospitalized, and no life-threatening complications were reported. The severity of the event was rated as mild. Table 39. Patients Reporting Suicidal Ideation as an Adverse Event After Viloxazine ER Exposure– Phase 2 and Phase 3 Studies Other Psychiatric Subject ID Dose Age Gender Severity SAE? Adverse Events Disposition 202 (b) (6) 100 mg 9 M Mild No None Completed 202 100 mg 9 M Mild No None Withdrawn (AE) 202 200 mg 7 M Mild No None Withdrawn by patient 202 200 mg 7 M Mild No None Completed 303 200 mg 6 M Mild Yes Tearfulness, insomnia Completed 303 200 mg 10 M Mild No None Completed Abbreviations: AE = adverse event; ER = extended release; SAE = severe adverse event One patient in the placebo group and one patient in the viloxazine ER group (302-(b) (6) ) reported suicidal ideation on the C-SSRS but did not report suicidal ideation as an adverse event.  Patient 302-(b) (6) : 15-year-old-female who was randomized to receive viloxazine ER 200 mg. She reported a wish to be dead on the C-SSRS on day 21. She did not experience any adverse events and completed the study. She had no psychiatric diagnoses other than ADHD and did not receive any concomitant medications. Three patients who were treated with viloxazine ER reported suicidal behavior on the C-SSRS but did not report suicidal behavior as an adverse event. None of the patients had a reported history of psychiatric diagnoses other than ADHD.  Patient 303-(b) (6) : 9-year-old male who was randomized to receive the 200 mg dose of viloxazine ER. He reported suicidal behavior on the C-SSRS at the Week-6 visit. No suicidal behavior was reported at the EOS visit. He experienced adverse events of cough and fatigue but did not report psychiatric adverse events. He completed the study.

 Patient 303-(b) (6) : 6-year-old male who was randomized to receive viloxazine ER 400 mg. He reported suicidal behavior at Weeks 4 and 5 but did not report any suicidal behavior by the end of the study. He experienced an adverse event of irritability as well as multiple nonpsychiatric adverse events (ear infection, pyrexia, nasal congestion, vomiting, headache, fatigue, seasonal allergy, and nasopharyngitis).

 Patient 303-(b) (6) : 7-year-old male who was randomized to receive viloxazine ER 200 mg. He reported suicidal behavior at Week 2. He did not complete the study (was lost to

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follow up) but did not report suicidal behavior at his last study visit (Week 6). He experienced adverse events including irritability, insomnia, somnolence, and limb abscess. Two patients receiving viloxazine ER reported suicidal behavior as adverse events in the placebo-controlled trials and their case narratives are summarized below.  Patient 303(b) (6) : 10-year-old female with a history of depression and anxiety who reported frequent thoughts of killing herself with a knife 55 days after starting treatment with viloxazine ER (400 mg dose). She waited until her mother fell asleep and took a knife from kitchen with the intent of killing herself. Ultimately, she did not harm herself with the knife and went back to bed. She was subsequently seen at a crisis center and discharged. A similar event reportedly occurred 1 month after treatment initiation but was not disclosed until the second event. The patient also reported history of suicidal ideation prior to study enrollment that she had not disclosed. The patient completed the study. In addition to suicidal behavior, adverse events reported during treatment included somnolence, irritability, and abdominal discomfort. No concomitant medications or psychiatric conditions other than ADHD were reported. This patient did report suicidal ideation at screening on the C-SSRS and at the end of study visit.

 Patient 304-(b) (6) : 15-year-old male with history of anger outbursts and emotional lability but no other psychiatric conditions besides ADHD reported on medical history. No concomitant medications were reported. He was admitted to a psychiatric unit approximately 7 weeks after starting treatment with viloxazine ER 400 mg for an unwitnessed suicide attempt. The patient had reportedly wrapped the wire of his headphones around his neck in an attempt to strangle himself. In addition to suicidal behavior, adverse events reported during treatment included affect lability, fatigue, and polydipsia. He was discontinued from the study because of the suicide attempt and reportedly recovered. Of note, the patient did not report suicidal ideation or behavior on the C-SSRS at baseline or during the study. By the 120-day safety update (data cutoff July 31, 2019), 1116 patients had enrolled in the long- term safety extension study (812P310) and 1097 had received study medication during the open- label period. Of them, 18 patients reported suicidal ideation, 2 reported suicide attempts, 5 reported intentional self-injury, and 1 patient reported self-injurious ideation. In 11 patients, suicidal ideation or behavior was classified as an SAE. Nine patients were withdrawn from Study 812P310 because of suicidal ideation or behavior. The clinical information of the two patients who reported suicide attempts in Study 812P310 is below:  Patient 202-(b) (6) : 8-year-old male with a medical history of eczema, enlarged tonsils, oppositional defiant disorder, stuttering, allergies, myringotomy, and . His concomitant medications included cetirizine and melatonin. He received viloxazine ER 300 mg daily in the double-blind treatment period in Study 812P202. In the open-label extension, he was receiving viloxazine ER 200 mg when he made a suicide attempt. His mother reported that he attempted suicide by starving himself, stabbing himself with a pen, and falling on the floor. The patient stated that he was trying to commit suicide. Psychosocial stressors at the time of the event included teasing at school and parental divorce. He had been diagnosed with depression at some point after starting viloxazine ER treatment and was enrolled in psychotherapy. No change to the dose of viloxazine ER was made after the event 89 Integrated Review Template, version date 2019/10/16

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but the patient ultimately was discontinued from the trial because of an adverse event of major depression.

 Patient 302-(b) (6) : 16-year-old female. No narrative was provided for this case, although the suicide attempt was categorized as a serious adverse event. From a review of the safety databases, this patient had a reported medical history of ADHD, acne, and tympanoplasty. Her only concomitant medication was an oral contraceptive pill. The patient received placebo in the double-blind treatment phase of Study 812P302. She entered the open-label extension in (b) (6) and her dose was titrated from 200 mg to 600 mg. The patient reported suicide attempts on (b) (6) and (b) (6) . The drug was withdrawn in (b) (6) because of adverse events of major depressive disorder, suicidal ideation, and self-injurious behavior. She recovered from the suicide attempt and other adverse events.

Conclusion

In total, 12/1118 (1.2%) viloxazine ER-treated patients who participated in the placebo- controlled clinical trials experienced suicidal ideation or behavior, reported either as an adverse event or on the C-SSRS. In contrast 3/487 (0.6%) placebo-treated patients experienced suicidal ideation or behavior. Most of the viloxazine ER-treated patients who reported suicidal behaviors appeared to have a pre-enrollment history of mood problems or reported psychiatric adverse events during the study. Patients who reported suicidal ideation without suicidal behavior in general did not necessarily have a prior history of a mood disorder or report other psychiatric adverse events during treatment. Most patients who developed suicidal ideation recovered and were able to complete the study. Patients, caregivers, and healthcare professionals should be aware that suicidal ideation can arise in patients without a history thereof and without accompanying reports of mood disturbance. This serious and potentially unexpected risk can be communicated in the labeling by means of a boxed warning. Of note, atomoxetine, also a norepinephrine reuptake inhibitor, carries a boxed warning for risk of suicidal ideation. 7.6.3. Risk of Negative Effects on Weight and Growth

Issue

Patients receiving viloxazine ER more frequently reported diminished appetite, were less likely to gain weight, and were more likely to lose weight than patients receiving placebo.

Background

ADHD is a childhood-onset disorder and viloxazine ER is intended for chronic use in the pediatric population. Negative impacts on appetite and nutritional status could worsen concentration in pediatric patients with ADHD; increase the risk of general cognitive dysfunction, irritability, and fatigue; and affect immunologic, reproductive, and bone health. The review of this risk issue focused on the clinical significance of viloxazine ER’s effects on appetite, weight, and growth.

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Assessment

In nonclinical studies, viloxazine treatment caused dose-dependent decreases in body weight, weight gain, and/or food consumption (by up to 15% to 20% at high doses, which were approximately 2- to 3-fold the MRHD based on mg/m2 in children). The decreases occurred most often during the first few weeks after treatment initiation but were reversible. These effects are likely associated with the adrenergic pharmacology of the drug. Patients treated with viloxazine ER were more likely to report decreased appetite as an adverse event than were patients receiving placebo (7.2% versus 0.4%). Decreased weight was not commonly reported as an adverse event in the viloxazine ER group or the placebo group (1.1% versus 0.4%). However, patients in the viloxazine ER group had minimal change in weight over the course of treatment while patients in the placebo group on average gained weight. In Study 812P301, which included patients ages 6 to 11 years, the mean change from baseline weight was 0.4 kg in the viloxazine ER 100 mg group, 0.1 kg in the viloxazine ER 200 mg group, and 1.3 kg in the placebo group (Figure 20). Figure 20. Mean Change in Weight from Baseline (Study 812P301)

Source: advs.xpt. Created by the Clinical Data Scientist. In Study 812P303, which also included patients ages 6 to 11 years, the mean change from baseline was 0.3 kg in the viloxazine ER 200 mg group, -0.1 kg in the viloxazine ER 400 mg group, and 1.3 kg in the placebo group (Figure 21).

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Figure 21. Mean Change in Weight from Baseline (Study 812P303)

Source: advs.xpt. Created by the Clinical Data Scientist. In Study 812P302, which included patients ages 7 to 12 years, the mean change from baseline weight was 0 kg in the viloxazine ER 200 mg group, -0.4 kg in the viloxazine ER 400 mg group, and 1.6 kg in the placebo group (Figure 22). Figure 22. Mean Change in Weight from Baseline (Study 812P302)

Source: advs.xpt. Created by the Clinical Data Scientist.

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In Study 812P304, which also included patients ages 12 to 17 years, the mean change from baseline was 0 kg in the viloxazine ER 400 mg group, -0.2 kg in the viloxazine ER 600 mg group, and 1.3 kg in the placebo group (Figure 23). Figure 23. Mean Change in Weight from Baseline (Study 812P304)

Source: advs.xpt. Created by the Clinical Data Scientist. Overall, the mean change from baseline weight in patients treated with viloxazine ER in the phase 3 controlled studies was 0.2 kg in patients ages 6 to 11 years (compared to 1 kg in the placebo group). The mean change from baseline in patients ages 12 to 17 years treated with viloxazine ER was -0.17 kg (compared to 1.5 kg in the placebo group). As discussed in Section Error! Reference source not found., the review team concluded that (b) (4) . The mean change in weight in adolescents receiving the 200 mg and 400 mg doses was -0.16 kg. The mean change from baseline weight in all patients receiving viloxazine ER was 0.04 kg (compared to 1.2 kg in patients receiving placebo). In addition, patients on viloxazine ER were more likely to have a ≥7% decrease in body weight over the course of the short-term safety and efficacy studies (Table 40). Table 40. Percentage of Patients With a ≥7% Decrease in Body Weight, Phase 3 Placebo- Controlled Trials Total Total Viloxazine 100 mg Viloxazine 200 mg Viloxazine 400 mg Viloxazine 600 mg Viloxazine Placebo (N=154) (N=367) (N=305) (N=99) (N=925) (N=463) n (%) n (%) n (%) n (%) n (%) n (%) 2 (1) 9 (3) 5 (2) 4 (4) 20 (2) 3 (1) Data from the long-term study are limited by the number of dropouts and the lack of a control group but suggest that patients taking viloxazine have a decreased growth trajectory. Patients who were still enrolled in Study 812P310 at 12 months had on average gained 2.9 kg and grown

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4.4 cm over the course of the year. The mean increase in BMI was 0.3 kg/m2 over 12 months. However, the BMI, weight, and height-for-age percentiles declined over time (Table 41). Table 41. Growth Parameters from Baseline to Month 12 (Study 812P310) Mean Change Median from Change from Sample Median Baseline Baseline Parameter Visit1 Size Mean (SD) (Min, Max) (SD) (Min, Max) BMI-for-age 63.6 percentile Baseline 1096 58.6 (28.4) (0, 99.5) - - BMI-for-age 57.3 -2.2 percentile Month 3 810 54.6 (29.1) (0.1, 99) -4.1 (11.7) (-53.8, 47.4) BMI-for-age 57.3 -3.6 percentile Month 6 624 53.6 (29.5) (0, 99) -5.2 (13.8) (-66.6, 35.2) BMI-for-age 54.8 -4 percentile Month 9 491 53.2 (29.6) (0.2, 98.7) -5.8 (14.7) (-65.4, 42.9) BMI-for-age 56.3 -4.1 percentile Month 12 339 52.9 (29.2) (0, 99.9) -5.1 (16.8) (-71.7, 85.4) Body Mass 17.9 Index (kg/m2) Baseline 1096 18.7 (3.4) (11.6, 36.8) Body Mass 17.8 -0.1 Index (kg/m2) Month 3 810 18.5 (3.5) (12.8, 32.3) -0.2 (0.9) (-4.8, 4.9) Body Mass 17.6 -0.1 Index (kg/m2) Month 6 624 18.5 (3.6) (12.4, 33.3) -0.1 (1.2) (-4.5, 6.9) Body Mass 17.6 0 Index (kg/m2) Month 9 491 18.6 (3.6) (12.8, 33.3) 0 (1.3) (-5.2, 5.9) Body Mass 17.7 0.1 Index (kg/m2) Month 12 339 18.8 (4.5) (12.7, 76.3) 0.3 (3.3) (-5.2, 61.2) Height-for-age 55 percentile Baseline 1096 53.8 (29) (0, 100) - - Height-for-age 52.2 -1.2 percentile Month 3 810 52.3 (29.1) (0, 100) -1.2 (5.9) (-23, 68) Height-for-age 50.3 -1.7 percentile Month 6 624 51.2 (29) (0, 100) -2.3 (8.2) (-40.9, 60.7) Height-for-age 50.1 -1.9 percentile Month 9 491 50.5 (29.7) (0, 100) -2.7 (9.5) (-49.6, 32.2) Height-for-age 46.6 -2.6 percentile Month 12 339 49.2 (30.2) (0, 99.4) -3.9 (10.3) (-39.4, 36.8) 143.9 Height (cm) Baseline 1096 145.3 (17.3) (106.6, 191.8) 144.5 0.8 Height (cm) Month 3 810 146.1 (17.2) (106.6, 190.5) 1 (1.4) (-4, 13.6) 145.1 2 Height (cm) Month 6 624 146.5 (17.2) (106.8, 192) 2.1 (1.9) (-5.9, 16.5) 145.6 3 Height (cm) Month 9 491 147.1 (17) (108.1, 192) 3.3 (2.4) (-5.9, 12.7) 147.3 4 Height (cm) Month 12 339 147.8 (16.4) (108.1, 187.9) 4.4 (2.8) (-2.6, 15.2) Weight-for-age 61.5 percentile Baseline 1096 58.4 (27.5) (0.1, 99.3) - - Weight-for-age 57.8 -2.4 percentile Month 3 810 55 (28.3) (0.3, 99.2) -3.3 (8) (-44.7, 34.6)

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Mean Change Median from Change from Sample Median Baseline Baseline Parameter Visit1 Size Mean (SD) (Min, Max) (SD) (Min, Max) Weight-for-age 57.3 -3.6 percentile Month 6 624 53.7 (28.6) (0.1, 99.5) -4.6 (9.8) (-47.6, 30) Weight-for-age 55.4 -4 percentile Month 9 491 53.2 (28.7) (0.1, 98.9) -5.2 (10.9) (-46.2, 51.6) Weight-for-age 53.5 -5.1 percentile Month 12 339 52 (28.7) (0.5, 100) -5.2 (13) (-46.5, 88.6) 37.6 Weight (kg) Baseline 1096 41.1 (15.9) (18.3, 96.2) 37.5 0.2 Weight (kg) Month 3 810 41.2 (16) (18.4, 96.3) 0.2 (1.9) (-9.2, 12.3) 37.5 0.7 Weight (kg) Month 6 624 41.4 (16) (19.3, 96.2) 0.8 (2.6) (-8.6, 16.7) 37.2 1.3 Weight (kg) Month 9 491 41.8 (16) (19.7, 98.9) 1.7 (3.2) (-9.1, 16) 38 2.1 Weight (kg) Month 12 339 42.4 (16.3) (20.2, 156) 2.9 (7.1) (-8.2, 128) Source: advs.xpt. Software, R. Created by the Clinical Data Scientist; modified by Clinical Review Team. 1 Unscheduled visits are not included. Data cutoff July 31, 2019. Abbreviations: BMI = body mass index

Conclusion

Pediatric patients, particularly prepubertal patients, are expected to demonstrate gains in weight and height. The available data raise the possibility that viloxazine ER slows the velocity of weight and height gains, although interpretation of the long-term data is hampered by the lack of a control group. Currently approved medications for ADHD—stimulants and atomoxetine—have also been associated with negative effects on growth parameters. Healthcare professionals who are considering viloxazine ER as a treatment option for ADHD in the pediatric population should be informed of the possibility that viloxazine ER will impact weight and growth. The review team has determined that including this risk in Section 5 (Warnings and Precautions) is appropriate. In addition, decreased appetite will be listed as a common adverse reaction in Section 6. 7.6.4. Risk of Heart Rate and Blood Pressure Changes

Issue

The review team assessed the potential risk of clinically significant heart rate and blood pressure changes associated with viloxazine ER because of the drug’s known adrenergic effects.

Background

Viloxazine ER is a norepinephrine reuptake inhibitor. Other medications with adrenergic effects have been associated with increases in heart rate and blood pressure. Approved labeling for stimulant medications cautions that CNS stimulants cause an increase in blood pressure (mean

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increase of about 2 to 4 mm Hg) and heart rate (mean increase of about 3 to 6 bpm) and advises monitoring of all patients for potential tachycardia and hypertension. The labeling for atomoxetine, another norepinephrine reuptake inhibitor, cautions that use may be associated with heart rate and blood pressure increases, orthostasis, and syncope, and that Raynaud’s phenomenon has been reported. Healthcare professionals are advised to exercise caution in patients with hypertension, tachycardia, cardiovascular disease, or cerebrovascular disease. Pulse and blood pressure should be measured at baseline, following dose increases, and periodically while on atomoxetine therapy. In pediatric placebo-controlled trials of atomoxetine, atomoxetine-treated patients experienced a mean heart rate increase of 6 bpm. Also, 2.5% of patients had heart rate increases of at least 25 bpm and a heart rate of 110 bpm (compared with 0.2% of patients on placebo). Tachycardia was identified as an adverse event in 0.3% of atomoxetine-treated patients and no placebo patients. Pediatric patients treated with atomoxetine experienced mean increases of about 1.6 mmHg and 2.4 mmHg in systolic and diastolic blood pressures, respectively, as compared with placebo. At the EOS visit, 4.8% of atomoxetine-treated patients had an elevated systolic blood pressure (compared with 3.5% of placebo-treated patients) and 4% had an elevated diastolic blood pressure (compared with 1.1% of placebo-treated patients). The mean increase in heart rate in adult patients treated with atomoxetine in placebo-controlled trials was 5 bpm. Adult patients taking atomoxetine had a mean systolic blood pressure increase of 2 mmHg and a mean diastolic blood pressure increase of 1 mg Hg. Also, 2.2% of adult patients treated with atomoxetine had a systolic blood pressure of ≥150 mmHg at the final study visit (compared with 1% of patients on placebo); 0.4% had a diastolic blood pressure of ≥100 mmHg (compared with 0.5% of patients on placebo). The evaluation of this review issue focused on assessment of the clinical meaningfulness of the heart rate and blood pressure changes observed in the placebo-controlled phase 3 trials of viloxazine ER. The review also considered how the vital sign changes observed in the viloxazine ER development program compare to those associated with stimulants and atomoxetine. However, no study directly comparing the safety of viloxazine ER and these drug products was performed and so no definitive conclusion about relative safety can be reached.

Assessment

Heart Rate

In the phase 3 placebo-controlled studies, 1.7% of patients treated with viloxazine ER reported tachycardia or increased heart rate as a treatment-emergent adverse event, compared with no patient in the placebo group. Bradycardia was not reported as an adverse event. The mean change in heart rate from baseline to EOS ranged from 2.4 to 6.3 bpm in patients treated with viloxazine ER across the dose groups; the mean heart range change in patients receiving placebo ranged from 0 to 1 bpm. Higher doses of viloxazine ER were associated with greater mean increases in heart rate (Table 42, Table 43, Table 44, and Table 45). The mean change in heart rate from baseline to EOS in all patients receiving viloxazine ER was 4.2 bpm with an SD of 13 mmHg, compared with 0.4 bpm (SD 10.8 mmHg) in patients on placebo.

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Table 42. Mean Change in Heart Rate (Study 812P301) SPN-812 100 mg SPN-812 200 mg SPN-812 Placebo (N=154) (N=161) (N=159) Mean Change Mean Change Mean Change Mean from Baseline Mean from Baseline Mean from Baseline Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Heart Rate Week 6 84.5 85.6 83.1 (beats/min) (EOS) 139 (11.5) 2.4 (12) 146 (13.6) 3.7 (13.9) 142 (10.6) 0 (10.4) 1 Source: advs.xpt. Does not include unscheduled visits. Created by the Clinical Data Scientist and Clinical Reviewer. Heart rate reference range, 70 to 120 beats per minute Abbreviations: EOS = end of study; SPN = viloxazine Table 43. Mean Change in Heart Rate (Study 812P302) SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=99) (N=105) (N=104) Mean Change Mean Change Mean Change Mean from Baseline Mean from Baseline Mean from Baseline Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Heart Rate Week 6 81.2 80.2 77 (beats/min) (EOS) 89 (11.6) 2.7 (13.4) 97 (12.7) 4.5 (12.9) 102 (11.3) 0 (10.9) Source: advs.xpt. Does not include unscheduled visits. Created by the Clinical Data Scientist and Clinical Reviewer. Heart rate reference range, 60 to 100 beats per minute Abbreviations: EOS = end of study; SPN = viloxazine Table 44. Mean Change in Heart Rate (Study 812P303) SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=107) (N=100) (N=103) Mean Change Mean Change Mean Change Mean from Baseline Mean from Baseline Mean from Baseline Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Heart Rate Week 8 84.4 86.8 83.2 (beats/min) (EOS) 99 (13.5) 5.7 (11.8) 84 (14.6) 5.2 (13.3) 93 (10.2) 1 (11) Source: advs.xpt. Does not include unscheduled visits. Created by the Clinical Data Scientist and Clinical Reviewer. Heart rate reference range, 70 to 120 beats per minute Abbreviations: EOS = end of study; SPN = viloxazine Table 45. Mean Change in Heart Rate (Study 812P304) SPN-812 400 mg SPN-812 600 mg SPN-812 Placebo (N=100) (N=99) (N=97) Mean Change Mean Change Mean Change Mean from Baseline Mean from Baseline Mean from Baseline Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Heart Rate Week 7 81.4 82.8 75.6 (beats/min) (EOS) 91 (13.6) 4.9 (12.1) 90 (12.3) 6.3 (14.4) 89 (12.3) 0.5 (11) Source: advs.xpt. Does not include unscheduled visits. Created by the Clinical Data Scientist and Clinical Reviewer. Heart rate reference range, 60 to 100 beats per minute Abbreviations: EOS = end of study; SPN = viloxazine In Studies 812P301 and 812P303, which enrolled patients ages 6 to 11 years, the reference range for heart rate was 70 to 120 bpm. In Study 812P301, two patients receiving viloxazine ER 200 mg had a heart rate of >120 bpm at EOS. In Study 812P303, three patients (receiving viloxazine ER 200 or 400 mg) had a heart rate of >120 bpm at EOS. No patients in the placebo group in either study had elevated heart rates at the EOS visit. In Study 812P301, the percentage of patients with a heart rate of <70 bpm decreased by the EOS visit in both dosage groups, but there was no change in the placebo group. In Study 812P303, the percentage of patients with a heart rate of <70 bpm decreased in all treatment groups by EOS (Table 46 and Table 47).

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Table 46. Heart Rate Out-of-Range (Study 812P301) SPN-812 ER 100 mg SPN-812 ER 200 mg Placebo (N=154) (N=161) (N=159) Parameter Visit N Low % High% N Low%High% N Low%High% Heart Rate 154 21 14 0 0 161 22 14 0 0 159 12 8 0 0 (beats/min) Baseline Heart Rate Week 6 139 11 8 0 0 146 15 10 2 0 142 11 8 0 0 (beats/min) (EOS) Source: advs.xpt. Created by the Clinical Data Scientist and Clinical Reviewer. Heart rate reference range, 70 to 120 beats per minute Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine Table 47. Heart Rate Out-of-Range (Study 812P303) SPN-812 ER 200 mg SPN-812 ER 400 mg Placebo (N=107) (N=100) (N=103) Parameter Visit N Low % High% N Low%High% N Low%High% Heart Rate 107 19 18 0 0 100 18 18 0 0 103 13 13 0 0 (beats/min) Baseline Heart Rate Week 8 99 13 13 2 2 84 9 11 1 1 93 7 8 0 0 (beats/min) (EOS) Source: advs.xpt. Created by the Clinical Data Scientist and Clinical Reviewer. Heart rate reference range, 70 to 120 beats per minute Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine In Studies 812P302 and 812P304, which enrolled patients ages 12 to 17 years, the reference range for heart rate was 60 to 100 bpm. In Study 812P302, 4.5% of patients in the viloxazine ER 200 mg group and 5.2% of patients in the 400 mg group had a heart rate of >100 bpm at the EOS visit, compared with 2.9% of patients in the placebo group. In Study 812P304, 7.7% of patients in the viloxazine ER 400 mg group and 10% of patients in the 600 mg group had a heart rate of >100 bpm at EOS, compared with 1.1% of patients in the placebo group. A higher proportion of patients on placebo in both studies had a heart rate of <60 bpm both at baseline and at EOS. Table 48. Heart Rate Out-of-Range (Study 812P302) SPN-812 ER 200 mg SPN-812 ER 400 mg Placebo (N=99) (N=105) (N=104) Parameter Visit N Low % High% N Low%High% N Low%High% Heart Rate 99 3 3 2 2 105 6 6 2 2 104 6 6 0 0 (beats/min) Baseline Heart Rate Week 6 89 1 1 4 5 97 4 4 5 5 102 5 5 3 3 (beats/min) (EOS) Source: advs.xpt. Created by the Clinical Data Scientist and Clinical Reviewer. Heart rate reference range, 60 to 100 beats per minute Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine Table 49. Heart Rate Out-of-Range (Study 812P304) SPN-812 ER 400 mg SPN-812 ER 600 mg Placebo (N=100) (N=99) (N=97) Parameter Visit N Low % High% N Low%High% N Low%High% Heart Rate 100 5 5 3 3 99 8 8 1 1 97 10 10 1 1 (beats/min) Baseline Heart Rate Week 7 91 2 2 7 8 90 1 1 9 10 89 6 7 1 1 (beats/min) (EOS) Source: advs.xpt. Created by the Clinical Data Scientist and Clinical Reviewer. Heart rate reference range, 60 to 100 beats per minute Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine

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Patients treated with viloxazine ER were more likely than those treated with placebo to have potentially clinically meaningful increases in heart rate (i.e., increases in heart rate ≥15 bpm or 25 bpm) at the EOS visit. Of note, a change of ≥25 bpm was observed in ≥5% of patients in all viloxazine ER dosage groups and was most notable in the 600 mg group, in which 10% of patients had an increase in heart rate of that magnitude (Table 50 and Table 51).

Table 50. Patients in Phase 3 Controlled Studies with a ≥15 BPM Increase in Heart Rate at EOS Number of Patients Treatment Group n (%) Placebo (N=426) 41(10) Viloxazine ER 100 mg (N=139) 20(14) Viloxazine ER 200 mg (N=334) 69(21) Viloxazine ER 400 mg (N=272) 62(23) SPN-812 ER 600 mg (N=90) 28(31) Source: advs.xpt. Created by the Clinical Reviewer. Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine Table 51. Patients in Phase 3 Controlled Studies with a ≥25 BPM Increase in Heart Rate at EOS Number of Patients Treatment Group n (%) Placebo (N=426) 6(1) Viloxazine ER 100 mg (N=139) 7(5) Viloxazine ER 200 mg (N=334) 20(6) Viloxazine ER 400 mg (N=272) 16(6) SPN-812 ER 600 mg (N=90) 9(10) Source: advs.xpt. Created by the Clinical Reviewer. Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine Overall, viloxazine ER appeared to have a consistent and dose-related effect on heart rate across the phase 3 controlled studies. Based on the data available in the viloxazine ER studies, the mean increases in heart rate may be comparable to those with atomoxetine and stimulants. However, these studies did not directly compare viloxazine ER to other approved ADHD medications.

Systolic Blood Pressure

Hypertension or increased blood pressure was reported as an adverse event in 0.8% of patients receiving viloxazine ER in the phase 3 controlled trials and 0.2% of patients on placebo. Hypotension was reported in 0.3% of patients receiving viloxazine ER but was not reported in any patients who received placebo. The mean change in systolic blood pressure ranged from -0.6 mm Hg to 2.8 mmHg in the viloxazine ER groups and -0.3 mmHg to 1.5 mmHg in the placebo group (Table 52, Table 53, Table 54, and Table 55). The mean change from baseline to EOS in systolic blood pressure among all patients receiving viloxazine ER was 0.8 mmHg (SD 9.9 mmHg), which was comparable to that in patients on placebo (0.7 mmHg, SD 10.1 mmHg).

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Table 52. Mean Change from Baseline in Systolic Blood Pressure (Study 812P301) SPN-812 100 mg SPN-812 200 mg SPN-812 Placebo (N=154) (N=161) (N=159) Mean Mean Mean Change Change Change from from from Mean Baseline Mean Baseline Mean Baseline Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Systolic Blood Week 6 106.8 105.4 106.3 Pressure (mmHg) (EOS) 139 (10.2) 0.4 (11) 146 (11) 0.5 (10.4) 142 (9) 1.3 (10.1) Source: advs.xpt. Created by the Clinical Data Scientist and Clinical Reviewer. 1 Does not include unscheduled visits. Systolic blood pressure reference range, 90 to 120 mmHg Abbreviations: EOS = end of study; SPN = viloxazine Table 53. Mean Change from Baseline in Systolic Blood Pressure (Study 812P302) SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=99) (N=105) (N=104) Mean Mean Mean Change Change Change from from from Mean Baseline Mean Baseline Mean Baseline Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Systolic Blood Week 6 114.2 114.3 112 Pressure (mmHg) (EOS) 89 (11) -0.3 (9.9) 97 (9.7) 1.1 (9.2) 102 (9.7) -0.3 (10.2) Source: advs.xpt. Created by the Clinical Data Scientist and Clinical Reviewer. 1 Does not include unscheduled visits. Systolic blood pressure reference range, 90 to 135 mmHg Abbreviations: EOS = end of study; SPN = viloxazine Table 54. Mean Change from Baseline in Systolic Blood Pressure (Study 812P303) SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=107) (N=100) (N=103) Mean Mean Mean Change Change Change from from from Mean Baseline Mean Baseline Mean Baseline Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Systolic Blood Week 8 103.6 105.9 104 Pressure (mmHg) (EOS) 99 (9.3) -0.6 (9.8) 84 (9.3) 2.8 (8.9) 93 (9.4) 0.3 (10.3) Source: advs.xpt. Created by the Clinical Data Scientist and Clinical Reviewer. 1 Does not include unscheduled visits. Systolic blood pressure reference range, 90 to 120 mmHg Abbreviations: EOS = end of study; SPN = viloxazine Table 55. Mean Change from Baseline in Systolic Blood Pressure (Study 812P304) SPN-812 400 mg SPN-812 600 mg SPN-812 Placebo (N=100) (N=99) (N=97) Mean Mean Mean Change Change Change from from from Mean Baseline Mean Baseline Mean Baseline Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Systolic Blood Week 7 112.8 113.9 112.9 Pressure (mmHg) (EOS) 91 (9.3) 0.5 (9.5) 90 (9.5) 2.5 (9.8) 89 (9.2) 1.5 (9.9) Source: advs.xpt. Created by the Clinical Data Scientist and Clinical Reviewer. 1 Does not include unscheduled visits. Systolic blood pressure reference range, 90 to 135 mmHg Abbreviations: EOS = end of study; SPN = viloxazine 100 Integrated Review Template, version date 2019/10/16

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The reference range for systolic blood pressure was 90 mmHg to 120 mmHg for patients ages 6 to 11 years (Studies 812P301 and 812P303). The percentage of patients with an out-of-range systolic blood pressure was variable across the two trials, both in patients receiving viloxazine ER and placebo (Table 56 and Table 57). Table 56. Systolic Blood Pressure Out-of-Range (Study 812P301) SPN-812 ER 100 mg SPN-812 ER 200 mg Placebo (N=154) (N=161) (N=159) Parameter Visit N Low % Hi % N Low % Hi % N Low % Hi % Systolic Blood 154 6 4 14 9 161 16 10 10 0.1 159 11 7 13 8 Pressure (mmHg) Baseline Systolic Blood Week 6 139 4 3 14 10 146 9 6 10 0.1 142 4 3 9 6 Pressure (mmHg) (EOS) Source: Table created by the Clinical Data Scientist and Clinical Reviewer Systolic blood pressure reference range, 90 to 120 mm Hg Abbreviations: EOS = end of study; ER = extended release; Hi = high; SPN = viloxazine Table 57. Systolic Blood Pressure Out-of-Range (Study 812P303) SPN-812 ER 200 mg SPN-812 ER 400 mg Placebo (N=107) (N=100) (N=103) Parameter Visit N Low % Hi % N Low % Hi % N Low % Hi % Systolic Blood 107 3 3 7 7 100 2 2 2 2 103 4 4 5 5 Pressure (mmHg) Baseline Systolic Blood Week 8 99 3 3 3 3 84 2 2 4 5 93 5 5 5 5 Pressure (mmHg) (EOS) Source: Table created by the Clinical Data Scientist and Clinical Reviewer Systolic blood pressure reference range, 90 to 120 mm Hg Abbreviations: EOS = end of study; ER = extended release; Hi = high; SPN = viloxazine The reference range for systolic blood pressure was 90 to 135 mmHg for patients ages 12 to 17 years (Studies 812P302 and 812P304). In those studies, a small number of patients in all groups had systolic blood pressures outside the reference range (Table 58 and Table 59). Table 58. Systolic Blood Pressure Out-of-Range (Study 812P302) SPN-812 ER 200 mg SPN-812 ER 400 mg Placebo (N=99) (N=105) (N=104) Parameter Visit N Low % Hi % N Low % Hi % N Low % Hi % Systolic Blood 99 0 0 2 2 105 1 1 1 1 104 1 1 0 0 Pressure (mmHg) Baseline Systolic Blood Week 6 89 1 1 3 3 97 0 0 1 1 102 2 2 0 0 Pressure (mmHg) (EOS) Source: Table created by the Clinical Data Scientist and Clinical Reviewer Systolic blood pressure reference range, 90 to 135 mm Hg Abbreviations: EOS = end of study; ER = extended release; Hi = high; SPN = viloxazine Table 59. Systolic Blood Pressure Out-of-Range (Study 812P304) SPN-812 ER 400 mg SPN-812 ER 600 mg Placebo (N=100) (N=99) (N=97) Parameter Visit N Low % Hi % N Low % Hi % N Low % Hi % Systolic Blood 100 1 1 0 0 99 1 1 1 1 97 0 0 0 0 Pressure (mmHg) Baseline Systolic Blood Week 7 91 0 0 0 0 90 1 1 0 0 89 0 0 1 1 Pressure (mmHg) (EOS) Source: Table created by the Clinical Data Scientist and Clinical Reviewer Systolic blood pressure reference range, 90 to 135 mm Hg Abbreviations: EOS = end of study; ER = extended release; Hi = high; SPN = viloxazine

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Patients receiving viloxazine ER 600 mg were more likely to have an increase in systolic blood pressure of ≥10 mmHg at the EOS (Table 60). Otherwise, patients treated with viloxazine ER or placebo did not appreciably differ in terms of the proportion with potentially clinically significant increases in systolic blood pressure. Table 60. Patients with a ≥10 mmHg Change in Systolic Blood Pressure at EOS Number of Patients Treatment Group n (%) Placebo (N=426) 75(18) Viloxazine ER 100 mg (N=139) 23(17) Viloxazine ER 200 mg (N=334) 58(17) Viloxazine ER 400 mg (N=272) 50(18) SPN-812 ER 600 mg (N=90) 24(27) Source: advs.xpt. Created by the Clinical Reviewer. Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine Table 61. Patients with a ≥20 mmHg Change in Systolic Blood Pressure at EOS Number of Patients Treatment Group n (%) Placebo (N=426) 16(4) Viloxazine ER 100 mg (N=139) 7(5) Viloxazine ER 200 mg (N=334) 10(3) Viloxazine ER 400 mg (N=272) 9(3) SPN-812 ER 600 mg (N=90) 4(4) Source: advs.xpt. Created by the Clinical Reviewer. Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine Overall, the mean changes in systolic blood pressure in the phase 3 controlled trials were small, not clearly clinically meaningful, and comparable to those in the placebo group. Most patients receiving viloxazine ER maintained a systolic blood pressure within the reference range for their age group.

Diastolic Blood Pressure

The mean changes in diastolic blood pressure in the phase 3 placebo-controlled studies ranged from 1.2 mmHg to 3.4 mmHg in patients receiving viloxazine ER and -0.5 mmHg to 1.2 mmHg in patients receiving placebo (Table 62, Table 63, Table 64, and Table 65). The mean change from baseline to EOS in diastolic blood pressure was 2.4 mmHg (SD 9.2) in all patients receiving viloxazine ER, compared with 0.4 mmHg (SD, 8.5) in patients receiving placebo. Table 62. Mean Change from Baseline in Diastolic Blood Pressure (Study 812P301) SPN-812 100 mg SPN-812 200 mg SPN-812 Placebo (N=154) (N=161) (N=159) Mean Mean Mean Change Change Change from from from Mean Baseline Mean Baseline Mean Baseline Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Diastolic Blood Week 6 67.4 68.1 66 Pressure (mmHg) (EOS) 139 (7.7) 1.9 (8.5) 146 (8.5) 3.2 (9.5) 142 (8.1) 1 (8.8) Source: advs.xpt. Created by the Clinical Data Scientist and Clinical Reviewer. 1 Does not include unscheduled visits. Abbreviations: EOS = end of study; SPN = viloxazine

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Table 63. Mean Change from Baseline in Diastolic Blood Pressure (Study 812P302) SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=99) (N=105) (N=104) Mean Mean Mean Change Change Change from from from Mean Baseline Mean Baseline Mean Baseline Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Diastolic Blood Week 6 71.2 72.4 69 Pressure (mmHg) (EOS) 89 (6.6) 1.2 (8.4) 97 (7.7) 3 (9.3) 102 (7.8) -0.5 (8.5) Source: advs.xpt. Created by the Clinical Data Scientist and Clinical Reviewer. 1 Does not include unscheduled visits. Abbreviations: EOS = end of study; SPN = viloxazine Table 64. Mean Change from Baseline in Diastolic Blood Pressure (Study 812P303) SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=107) (N=100) (N=103) Mean Mean Mean Change Change Change from from from Mean Baseline Mean Baseline Mean Baseline Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Diastolic Blood Week 8 66.3 67.1 65.3 Pressure (mmHg) (EOS) 99 (7.8) 2.3 (8.9) 84 (8.1) 1.2 (9.6) 93 (7.6) -0.5 (8.6) Source: advs.xpt. Created by the Clinical Data Scientist and Clinical Reviewer. 1 Does not include unscheduled visits. Abbreviations: EOS = end of study; SPN = viloxazine Table 65. Mean Change from Baseline in Diastolic Blood Pressure (Study 812P304) SPN-812 400 mg SPN-812 600 mg SPN-812 Placebo (N=100) (N=99) (N=97) Mean Mean Mean Change Change Change from from from Mean Baseline Mean Baseline Mean Baseline Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Diastolic Blood Week 7 71.8 72.2 69.3 Pressure (mmHg) (EOS) 91 (7.5) 2.9 (10.5) 90 (7.9) 3.4 (9.2) 89 (7.5) 1.2 (7.8) Source: advs.xpt. Created by the Clinical Data Scientist and Clinical Reviewer. 1 Does not include unscheduled visits. Abbreviations: EOS = end of study; SPN = viloxazine The reference range for diastolic blood pressure for patients ages 6 to 11 was 50 to 80 mmHg (Studies 812P301 and 812P303). In Study 812P301, patients receiving viloxazine ER were not more likely than those receiving placebo to have an elevated diastolic blood pressure at EOS. In Study 812P303, patients in the placebo group were more likely to have an elevated diastolic blood pressure at baseline but less likely to have an elevated diastolic blood pressure at EOS than those receiving viloxazine ER 200 mg or 400 mg.

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Table 66. Diastolic Blood Pressure Out-of-Range (Study 812P301) SPN-812 ER 100 mg SPN-812 ER 200 mg Placebo (N=154) (N=161) (N=159) Parameter Visit N Low % High% N Low% High % N Low % High% Diastolic Blood 154 2 1 4 3 161 2 1 7 0 159 1 1 1 1 Pressure (mmHg) Baseline Diastolic Blood Week 6 139 1 1 4 3 146 2 1 13 0.1 142 0 0 7 5 Pressure (mmHg) (EOS) Source: Table created by the Clinical Data Scientist and Clinical Reviewer. Diastolic blood pressure reference range, 50 to 80 mmHg Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine Table 67. Diastolic Blood Pressure Out-of-Range (Study 812P303) SPN-812 ER 200 mg SPN-812 ER 400 mg Placebo (N=107) (N=100) (N=103) -Parameter Visit N Low % High% N Low%High % N Low % High% Diastolic Blood 107 3 3 2 2 100 0 0 3 3 103 2 2 5 5 Pressure (mmHg) Baseline Diastolic Blood Week 8 99 1 1 4 4 84 1 1 2 2 93 2 2 1 1 Pressure (mmHg) (EOS) Source: Table created by the Clinical Data Scientist and Clinical Reviewer Diastolic blood pressure reference range, 50 to 80 mmHg Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine The reference range for diastolic blood pressure for patients ages 12 to 17 was 64 to 83 mmHg (Studies 812P302 and 812P304). In both studies, a large number of patients had a diastolic blood pressure below the reference range cut-off (64 mmHg) at baseline and at EOS. However, only 4% of patients receiving viloxazine had a diastolic blood pressure of <60 mmHg at EOS (compared with 9.4% of patients receiving placebo) and no patients treated with viloxazine had a diastolic blood pressure of <50 mmHg at EOS. Patients in the viloxazine ER 400 mg and 600 mg groups were more likely to have a diastolic blood pressure of >83 mm Hg at EOS compared with those in the placebo group (Table 68 and Table 69). Table 68. Diastolic Blood Pressure Out-of-Range (Study 812P302) SPN-812 ER 200 mg SPN-812 ER 400 mg Placebo (N=99) (N=105) (N=104) Hig Parameter Visit N Low % h%NLow%High % N Low % High% Diastolic Blood Pressure (mmHg) Baseline 99 20 20 6 6 105 21 20 4 4 104 23 22 2 2 Diastolic Blood Week 6 Pressure (mmHg) (EOS) 89 10 11 3 3 97 13 13 9 9 102 25 25 6 6 Source: Table created by the Clinical Data Scientist and Clinical Reviewer Diastolic blood pressure reference range, 64 to 83 mmHg Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine

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Table 69. Diastolic Blood Pressure Out-of-Range (Study 812P304) SPN-812 ER 400 mg SPN-812 ER 600 mg Placebo (N=100) (N=99) (N=97) Hig Parameter Visit N Low % h%NLow%High % N Low % High% Diastolic Blood Pressure (mmHg) Baseline 100 29 29 4 4 99 19 19 2 2 97 31 32 4 4 Diastolic Blood Week 7 Pressure (mmHg) (EOS) 91 12 13 5 6 90 12 13 8 9 89 14 16 3 3 Source: Table created by the Clinical Data Scientist and Clinical Reviewer Diastolic blood pressure reference range, 64 to 83 mmHg Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine In addition, patients receiving viloxazine ER were more likely to have a potentially clinically meaningful increase in diastolic blood pressure (i.e., increase of ≥10 mmHg or 20 mmHg) than those receiving placebo (Table 70 and Table 71). Table 70. Patients with a ≥10 mmHg Change in Diastolic Blood Pressure at EOS Treatment Group Number of Patients % Placebo (N=426) 57 13% Viloxazine ER 100 mg (N=139) 26 19% Viloxazine ER 200 mg (N=334) 69 21% Viloxazine ER 400 mg (N=272) 58 21% SPN-812 ER 600 mg (N=90) 22 24% Source: advs.xpt. Created by the Clinical Reviewer. Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine Table 71. Patients with a ≥20 mmHg Change in Diastolic Blood Pressure at EOS Treatment Group Number of Patients % Placebo (N=426) 51% Viloxazine ER 100 mg (N=139) 32% Viloxazine ER 200 mg (N=334) 133% Viloxazine ER 400 mg (N=272) 104% SPN-812 ER 600 mg (N=90) 44% Source: advs.xpt. Created by the Clinical Reviewer. Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine In summary, viloxazine ER was associated with greater increases in diastolic blood pressure in the phase 3 controlled trials compared to placebo. These increases may be dose related, although the mean changes in diastolic blood pressure and the proportion of patients with out-of-range diastolic blood pressure were not strikingly different among the viloxazine ER dose groups. More than 20% of patients treated with viloxazine ER had potentially clinically significant changes in diastolic blood pressure at the EOS visit.

Long-term Data on Heart Rate and Blood Pressure

The review team examined data from Study 812P310 to assess whether any persistent changes in heart rate and blood pressure were evident over time. Study 812P310 is ongoing, but data up to the Month 12 visit were analyzed given the considerable decrease in the number of patients for whom data at later time points are available. At Month 12, 339 patients were in the safety study population. On average, the mean changes from baseline at Month 12 in systolic and diastolic blood pressures were <1 mmHg. The mean change in heart rate at Month 12 was 1.2 bpm in the supine position and 2.9 bpm in the standing position (Table 72).

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Table 72. Vital Signs by Visit, Safety Population (Study 812P310) Mean Change Median from Change from Sample Mean Median Baseline Baseline Parameter Visit1 Size (SD) (Min, Max) (SD) (Min, Max) Diastolic Blood Pressure- Seated/Supine (mmHg) Baseline 1094 68.3 (7.9) 69 (42, 97) Diastolic Blood Pressure- Seated/Supine (mmHg) Month 3 809 68.8 (7.8) 69 (48, 104) 0.4 (8.4) 0 (-31, 39) Diastolic Blood Pressure- Seated/Supine (mmHg) Month 6 624 68.9 (7.8) 69 (40, 94) 0.5 (8.7) 0 (-30, 34) Diastolic Blood Pressure- Seated/Supine (mmHg) Month 9 491 69.6 (7.3) 70 (48, 90) 1.1 (8.3) 1 (-26, 37) Diastolic Blood Pressure- Seated/Supine (mmHg) Month 12 339 68.7 (7) 68 (50, 89) 0.1 (8.9) 0 (-23, 32) Diastolic Blood Pressure- Standing (mmHg) Baseline 922 70.1 (8.1) 71 (31, 109) Diastolic Blood Pressure- Standing (mmHg) Month 3 809 70.8 (7.7) 71 (49, 99) 0.5 (8.1) 0 (-24, 45) Diastolic Blood Pressure- Standing (mmHg) Month 6 624 70.9 (7.7) 71 (48, 99) 0.3 (8.5) 0 (-22, 34) Diastolic Blood Pressure- Standing (mmHg) Month 9 491 71.9 (7.3) 72 (52, 96) 1.2 (8.5) 1 (-21, 34) Diastolic Blood Pressure- Standing (mmHg) Month 12 339 71.4 (7.3) 71 (49, 99) 0.8 (8.9) 0 (-22, 32) Heart Rate-Seated/Supine 83.2 (beats/min) Baseline 1094 (12.7) 83 (50, 127) Heart Rate-Seated/Supine 84.9 1.5 (beats/min) Month 3 809 (14.1) 84 (51, 138) (13.7) 2 (-48, 71) Heart Rate-Seated/Supine 1.9 (beats/min) Month 6 624 85.3 (13) 85 (54, 134) (12.2) 1 (-44, 42) Heart Rate-Seated/Supine 1.8 (beats/min) Month 9 491 85.5 (13) 86 (50, 136) (13.1) 2 (-37, 48) Heart Rate-Seated/Supine 85.1 1.2 (beats/min) Month 12 339 (13.2) 84 (55, 132) (12.5) 2 (-44, 40) Heart Rate-Standing 87.7 (beats/min) Baseline 921 (13.9) 88 (50, 150) Heart Rate-Standing 91.5 2.4 (beats/min) Month 3 809 (15.4) 92 (52, 143) (13.9) 2 (-46, 46) Heart Rate-Standing 2.7 (beats/min) Month 6 624 91.9 (14) 92 (53, 132) (13.2) 3 (-40, 49) Heart Rate-Standing 92.3 3.4 (beats/min) Month 9 491 (14.2) 92 (53, 140) (13.5) 3 (-59, 43) Heart Rate-Standing 92.3 (beats/min) Month 12 339 (14.2) 91 (59, 137) 2.9 (14) 4 (-63, 37) Systolic Blood Pressure- 108.3 Seated/Supine (mmHg) Baseline 1094 (10.3) 108 (70, 137) Systolic Blood Pressure- 108.4 Seated/Supine (mmHg) Month 3 809 (10.2) 108 (80, 138) 0.1 (10) 0 (-38, 44) Systolic Blood Pressure- 108.9 0.5 Seated/Supine (mmHg) Month 6 624 (9.5) 108 (80, 136) (10.4) 0 (-27, 36) Systolic Blood Pressure- 109.4 Seated/Supine (mmHg) Month 9 491 (9.6) 108 (82, 139) 1.2 (9.9) 0 (-33, 33)

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Mean Change Median from Change from Sample Mean Median Baseline Baseline Parameter Visit1 Size (SD) (Min, Max) (SD) (Min, Max) Systolic Blood Pressure- 108.5 0.2 Seated/Supine (mmHg) Month 12 339 (9.4) 109 (86, 136) (10.2) 0 (-29, 26) Systolic Blood Pressure- 109.1 Standing (mmHg) Baseline 922 (10.4) 109 (73, 147) Systolic Blood Pressure- 108.8 Standing (mmHg) Month 3 809 (9.7) 108 (80, 141) -0.3 (9.8) 0 (-42, 31) Systolic Blood Pressure- 109.2 Standing (mmHg) Month 6 624 (9.4) 109 (72, 140) 0 (10.6) 0 (-36, 36) Systolic Blood Pressure- 109.8 0.7 Standing (mmHg) Month 9 491 (9.4) 110 (80, 146) (10.9) 0 (-27, 35) Systolic Blood Pressure- 109.2 -0.4 Standing (mmHg) Month 12 339 (9.2) 110 (85, 135) (10.8) -2 (-27, 31) Source: advs.xpt; Software: R. Created by Clinical Data Scientist and Clinical Reviewer. Data cutoff July 31, 2019 (120-day safety update) At the Month 12 visit, 14.5% of patients had a ≥15 bpm change in baseline seated heart rate and 4% had a ≥25 bpm increase. Few patients ages 6 to 11 years had seated heart rates exceeding the upper limit of the reference range (120 bpm) compared to nearly 10% of patients ages 7 to 12 years. Standing heart rate was more likely to be elevated, with 8% of all patients experiencing a ≥25 bpm increase; 4% of patients ages 6 to 11 years and 20% of patients ages 12 to 17 years had a standing heart rate greater than the upper limit for age (Table 73). Table 73. Change from Baseline to Month 12 in Heart Rate (Study 812P310) ≥15 bpm CFB ≥25 bpm CFB HR >120 bpm HR >100 (All Patients) (All Patients) (Ages 6 to 11 Years) (Ages 12 to 17 Years) Heart rate (seated) 49/339 (15%) 14/339 (4%) 1/225 (0.4%) 11/114 (10%) Heart rate (standing) 47/339 (14%) 27/339 (8%) 9/225 (4%) 23/114 (20%) Source: advs.xpt. Created by the Clinical Reviewer. Abbreviations: CFB = change from baseline; HR = heart rate Few patients had a systolic blood pressure higher than the upper limit of the reference range or an increase in systolic blood pressure of ≥20 mmHg (Table 74).

Table 74. Change from Baseline to Month 12 in Systolic Blood Pressure (Study 812P310) SBP >120 mmHg SBP >135 mmHg ≥20 mmHg CFB (Ages 6 to 11 Years) (Ages 12 to 17 Years) SBP (seated) 13/339 (4%) 14/225 (6%) 1/114 (1%) Source: advs.xpt. Created by the Clinical Reviewer. Abbreviations: CFB = change from baseline (increase); SBP = systolic blood pressure Although <5% of patients had a diastolic blood pressure that exceeded the upper limit of the reference range at Month 12, 14% of patients had a diastolic blood pressure increase of ≥10 mmHg from baseline (Table 75).

Table 75. Change from Baseline to Month 12 in Diastolic Blood Pressure (Study 812P310) DBP >80 mmHg DBP >83 mmHg ≥10 mmHg CFB (Ages 6 to 11 Years) (Ages 12 to 17 Years) DBP (seated) 46/339 (14%) 11/225 (5%) 4/114 (4%) Source: advs.xpt. Created by the Clinical Reviewer. Abbreviations: CFB = change from baseline (increase); DBP = diastolic blood pressure

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Conclusion

Viloxazine ER was associated with a dose-dependent increase in heart rate of 2.4 to 6.3 bpm in the phase 3 controlled studies. Patients receiving viloxazine ER in the long-term, open-label safety extension also experienced increases in heart rate, although the change from baseline in heart rate at Month 12 was comparatively small (1.2 bpm seated and 2.9 bpm standing). Viloxazine ER was also associated with increases (1.2 mmHg to 3.4 mmHg) in diastolic blood pressure in the short-term phase 3 studies. In the long-term study, the mean change in diastolic blood pressure was less than 1 mmHg at Month 12, but 14% of patients had a potentially clinically meaningful increase in diastolic blood pressure (≥10 mmHg) from baseline. Viloxazine ER was not clearly linked to changes in systolic blood pressure. The labeling for viloxazine ER should inform healthcare professionals of the possibility of increased heart rate and diastolic blood pressure. Heart rate and blood pressure should be measured at baseline in patients receiving viloxazine ER and monitored during treatment. 7.6.5. Risk of Liver Injury

Issue

Reports of liver toxicity potentially related to the use of the immediate-release formulation of viloxazine have been found in postmarketing databases. Atomoxetine, another norepinephrine reuptake inhibitor, carries a warning regarding the risk of severe liver injury.

Background

The EudraVigilance, Vigibase, and FAERS databases contain reports of hepatobiliary disorders, including liver injury, that were possibly associated with immediate-release viloxazine exposure. Transaminase elevations were noted as a possible adverse reaction in the European labeling for viloxazine. However, case reports or other data regarding liver injury associated with viloxazine are not present in the published literature. No evidence of liver injury was detected in atomoxetine clinical trials, but rare cases of clinically significant liver injury that were considered probably or possibly related to atomoxetine have been reported in the postmarketing period. These reports included patients who presented with liver levels >20-fold the upper limit of normal (ULN) and jaundice with a bilirubin level >2-fold the ULN. The patients recovered upon atomoxetine discontinuation. Viloxazine ER has a similar mechanism of action to atomoxetine and the possibility of a class effect was considered. Nonclinical data and clinical data from the controlled clinical studies and the open-label extension study for viloxazine ER were examined for any signals of hepatoxicity. Also, postmarketing data from the immediate- release form of viloxazine were reviewed for cases of hepatobiliary disorders.

Assessment

Nonclinical Findings

In animal species (mouse, rat, and dog), repeat treatment of viloxazine caused hepatocellular hypertrophy and/or vacuolation in the liver. In addition, viloxazine caused small hepatocellular eosinophilic bodies or inclusion bodies in the liver in dog. These changes occurred at doses equal

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to or less than the MRHD (Table 76). Further staining and electron microscopy demonstrated that the vacuoles were primarily lipid droplet accumulation in hepatocytes and the inclusion bodies were likely due to hypertrophic endoplasmic reticulum. These changes did not correlate with any other histopathology lesions or significant changes in clinical chemistry indicative of liver injury and were reversible after drug free recovery period. Moreover, these changes did not lead to an increase in the incidence of liver tumors in the rodent carcinogenicity studies. Therefore, from a nonclinical perspective, these liver findings are likely adaptive in response to viloxazine administration and are not considered to be adverse. Table 76. Viloxazine-Related Liver Findings in Nonclinical Species and Corresponding Exposure Multiples Dose Exposure Multiples Species (mg/kg/day) Liver Findings (mg/m2)1 Mouse ≥130 ↑ hepatocellular hypertrophy and vacuolation (lipid ~1× accumulation) Rat ≥52 ↑ hepatocellular vacuolation (lipid accumulation) ~ 0.5× Dog ≥3.5 ↑ hepatocellular hypertrophy, vacuolation (lipid ~ 0.1× accumulation), and inclusion bodies (hypertrophic endoplasmic reticulum) Source: Modified/reformatted based on the data in the Applicant’s study reports 1 Safety margins are calculated using the average child body weight of 20 kg and conversion factor Km of 25

Adverse Events

No adverse events in the Hepatobiliary SOC were reported in the phase 2 or phase 3 controlled trials. No adverse events related to liver transaminase or bilirubin elevations were reported in the phase 2 study (812P202). Among the 925 patients who were exposed to viloxazine ER in the phase 3 controlled studies, the following non-serious TEAEs related to liver transaminase investigations were reported:  One patient (0.1%) reported increased hepatic enzyme levels  Six patients (0.6%) reported an increased alanine aminotransferase (ALT) level  Four patients (0.4%) reported an increased aspartate aminotransferase (AST) level The open-label safety extension study (812P310) included 1097 patients in the safety population; of them, five patients reported nonserious elevations in hepatobiliary laboratory assessments:  Two patients reported an increased ALT level  One patient reported an increased AST level  One patient reported an increased total bilirubin level  One patient reported an increased alkaline phosphatase level

Laboratory Assessments

The mean changes in hepatobiliary laboratory assessments in the phase 3 clinical trials were small and unlikely to be clinically meaningful (Table 77,Table 78, Table 79, and Table 80).

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Table 77. Hepatobiliary Assessments (Study 812P301) SPN-812 100 mg SPN-812 200 mg SPN-812 Placebo (N=154) (N=161) (N=159) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Alanine Aminotransferase 15.3 15 15.2 (U/L) Baseline 153 (6.5) 161 (5.2) 158 (6.9) Alanine Aminotransferase Week 6 15.8 0.4 16.9 2 15.3 0.1 (U/L) (EOS) 136 (8.3) (7.6) 138 (14.1) (13.8) 139 (5.8) (7) Alkaline Phosphatase 251.9 250.6 249.1 (U/L) Baseline 153 (74) 161 (71) 158 (61.4) Alkaline Phosphatase Week 6 250.5 1.3 249.5 3.2 253.4 5.9 (U/L) (EOS) 136 (69.5) (35.7) 137 (68) (57.9) 137 (63.1) (39.4) Aspartate Aminotransferase 26.4 25.7 25.8 (U/L) Baseline 153 (6.2) 161 (5.3) 158 (5.5) Aspartate Aminotransferase Week 6 26 -0.3 26.5 1 26.1 0.3 (U/L) (EOS) 136 (6.8) (5.1) 138 (16.8) (17.1) 139 (6.3) (5.5) 5.7 5.6 5.9 Bilirubin (µmol/L) Baseline 153 (3.6) 161 (3.3) 158 (4) Week 6 5.4 -0.3 5.3 -0.5 5.3 -0.6 Bilirubin (µmol/L) (EOS) 136 (2.8) (2.7) 138 (3) (2.5) 139 (2.8) (2.7) Direct Bilirubin 3.1 3.1 3.1 (µmol/L) Baseline 153 (0.3) 159 (0.3) 158 (0.5) Direct Bilirubin Week 6 3 0 3.1 0 3 0 (µmol/L) (EOS) 136 (0.3) (0.3) 138 (0.3) (0.3) 139 (0.3) (0.4) Source: ad b.xpt; Software, R. Created by the Clinical Data Scientist. 1 Unscheduled visits are not included. Reference ranges in patients ages 6 to 11 years: ALT, 5 to 30 U/L; AST, 0 to 47 U/L; a kaline phosphatase, 155 to 420; bilirubin, 2 to 21 µmol/L, direct bilirubin, 0 to 7 µmol/L Abbreviations: EOS = end of study; SPN = viloxazine Table 78. Hepatobiliary Assessments (Study 812P302) SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=99) (N=105) (N=104) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Alanine Aminotransferase 14.8 16.1 14.8 (U/L) Baseline 98 (5) 104 (8.2) 104 (8.9) Alanine Aminotransferase Week 6 15.6 0.8 18.1 1.9 14.6 -0.2 (U/L) (EOS) 86 (7.4) (6.6) 96 (12.4) (11.1) 102 (7.8) (6.4) Alkaline Phosphatase 210.5 207.7 206.2 (U/L) Baseline 98 (112.9) 103 (104.9) 104 (113) Alkaline Phosphatase Week 6 207 -4.5 197.7 -5.6 201.1 -2.1 (U/L) (EOS) 86 (106.8) (34.3) 95 (104) (31.9) 101 (109.6) (41.6)

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SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=99) (N=105) (N=104) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) 8.7 7.2 8.1 Bilirubin (µmol/L) Baseline 98 (6) 104 (5.7) 104 (6.4) Week 6 8.1 -0.7 6.2 -1.2 7.9 -0.3 Bilirubin (µmol/L) (EOS) 86 (7.4) (6.3) 96 (5) (3.6) 102 (6.9) (4.1) Aspartate Aminotransferase 21.3 21.5 20.4 (U/L) Baseline 98 (5.8) 104 (6.2) 104 (6.2) Aspartate Aminotransferase Week 6 21.3 -0.3 21.5 0.2 20 -0.4 (U/L) (EOS) 86 (6.4) (4.8) 96 (7.3) (7.5) 102 (5.8) (4.7) Direct Bilirubin 3.3 3.2 3.2 (µmol/L) Baseline 98 (0.7) 104 (0.6) 104 (0.7) Direct Bilirubin Week 6 3.2 -0.1 3.1 -0.1 3.2 0 (µmol/L) (EOS) 86 (0.6) (0.7) 95 (0.4) (0.6) 102 (0.6) (0.7) Source: ad b.xpt; Software, R. Created by the Clinical Data Scientist. 1 Unscheduled visits are not included Reference ranges in patients ages 12 to 17 years: ALT, 5 to 20 U/L; AST, 0 to 41 U/L; alkaline phosphatase, 110 to 630 U/L; bilirubin 2 to 21 µmol/L, direct bilirubin, 0 to 7 µmol/L Abbreviations: EOS = end of study; SPN = viloxazine Table 79. Hepatobiliary Assessments (Study 812P303) SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=107) (N=100) (N=103) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Alanine Aminotransferase 14.4 15 15.7 (U/L) Baseline 107 (4.9) 100 (6.1) 103 (6.3) Alanine Aminotransferase Week 8 15.1 0.7 16.2 1.1 15.6 -0.3 (U/L) (EOS) 97 (6) (6.1) 81 (10.5) (8.4) 92 (6.6) (7.1) Alkaline Phosphatase 240.2 253.6 238 (U/L) Baseline 107 (63.5) 100 (76.8) 103 (55.2) Alkaline Phosphatase Week 8 240.7 5.5 247 -1.8 246.5 11.5 (U/L) (EOS) 97 (65.8) (42.9) 81 (67.3) (52.7) 92 (60.5) (39.6) Aspartate Aminotransferase 25.8 26 26.8 (U/L) Baseline 107 (5.4) 100 (5.2) 103 (6) Aspartate Aminotransferase Week 8 26.5 0.8 25.8 -0.2 26.3 -0.4 (U/L) (EOS) 97 (8.6) (7.7) 81 (6.4) (5.4) 92 (6.5) (5.5) 5.5 6.1 5.8 Bilirubin (µmol/L) Baseline 107 (3.2) 100 (3.5) 103 (3.2)

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SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=107) (N=100) (N=103) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Week 8 4.8 -0.7 5.7 -0.8 5.9 0.5 Bilirubin (µmol/L) (EOS) 97 (2.4) (2.8) 81 (3.7) (2.9) 92 (3.6) (2.5) Direct Bilirubin 3 3.1 3.1 (µmol/L) Baseline 107 (0.2) 100 (0.3) 103 (0.4) Direct Bilirubin Week 8 3 0 3.1 0 3.1 0 (µmol/L) (EOS) 97 (0.1) (0.2) 81 (0.4) (0.4) 92 (0.4) (0.4) Source: ad b.xpt; Software, R. Created by the Clinical Data Scientist. 1Unscheduled visits are not included Reference ranges in patients ages 6 to 11 years: ALT, 5 to 30 U/L; AST, 0 to 47 U/L; a kaline phosphatase, 155 to 420 U/L; bilirubin, 2 to 21 µmol/L; direct bilirubin, 0 to 7 µmol/L Abbreviations: EOS = end of study; SPN = viloxazine Table 80. Hepatobiliary Assessments (Study 812P304) SPN-812 400 mg SPN-812 600 mg SPN-812 Placebo (N=100) (N=99) (N=97) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Alanine Aminotransferase 15.1 14.6 14.2 (U/L) Baseline 100 (8.1) 99 (5.6) 97 (7.9) Alanine Aminotransferase Week 7 20.2 5 16.9 2.3 13.9 -0.5 (U/L) (EOS) 86 (16.5) (16.2) 88 (9.6) (9.6) 88 (6.6) (5.2) Alkaline Phosphatase 206.8 223.3 204.1 (U/L) Baseline 100 (116.5) 99 (106.3) 97 (114.4) Alkaline Phosphatase Week 7 207.2 3.1 219.5 2.6 194.1 -8.6 (U/L) (EOS) 86 (118.3) (36.6) 88 (109.1) (28.8) 88 (108.6) (31.9) Aspartate Aminotransferase 21.1 21.4 20.2 (U/L) Baseline 100 (6.2) 99 (5.4) 97 (5.5) Aspartate Aminotransferase Week 7 23.1 2.3 20.9 -0.1 19.5 -0.5 (U/L) (EOS) 86 (8.8) (9) 88 (6.5) (5.6) 88 (5.4) (4) 7.6 8.3 8 Bilirubin (µmol/L) Baseline 100 (4.3) 99 (4.6) 97 (5.3) Week 7 6.2 -1.4 6.6 -1.8 7.7 -0.2 Bilirubin (µmol/L) (EOS) 86 (3.6) (3.4) 88 (3.7) (3.5) 88 (4.5) (3.8) Direct Bilirubin 3.1 3.2 3.2 (µmol/L) Baseline 100 (0.6) 99 (0.6) 97 (0.6) Direct Bilirubin Week 7 3.8 0.7 3.1 -0.1 3.2 0 (µmol/L) (EOS) 86 (7.1) (7) 88 (0.3) (0.4) 88 (0.6) (0.5) Source: ad b.xpt; Software, R. Created by the Clinical Data Scientist. 1 Unscheduled visits are not included Reference ranges in patients ages 12 to 17 years: ALT, 5 to 20 U/L; AST, 0 to 41 U/L; alkaline phosphatase, 110 to 630 U/L; bilirubin 2 to 21 µmol/L; direct bilirubin, 0 to 7 µmol/L Abbreviations: EOS = end of study; SPN = viloxazine In Studies 812P301 and 812P302, no clear difference in the frequency of out of range hepatobiliary laboratory assessments between the viloxazine ER and placebo groups was 112 Integrated Review Template, version date 2019/10/16

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observed. In Study 812P303, 4.9% of patients receiving viloxazine ER 400 mg had increased ALT values (compared to 2.2% of the placebo group). In Study 812P304, patients receiving viloxazine ER were more likely that patients in the placebo group to have hepatic enzyme values that were higher than the upper limit of the reference range. ALT elevations were seen in 14% of patients receiving viloxazine ER 400 mg and 11.4% of patients receiving viloxazine ER 600 mg. AST elevations were seen in 7% of patients receiving viloxazine ER 400 mg and 2.3% of patients receiving viloxazine ER 600 mg (Table 81, Table 82, Table 83, and Table 84). Table 81. Out-of-Range Hepatobiliary Assessments (Study 812P301) SPN-812 ER 100 mg SPN-812 ER 200 mg Placebo (N=154) (N=161) (N=159) Parameter Visit N Low % High% NLow%High% N Low % High% Alanine Aminotransferase (U/L) Baseline 153 0 0 5 3 161 0 0 3 2 158 0 0 5 3 Alanine Aminotransferase Week 6 (U/L) (EOS) 136 0 0 7 5 138 0 0 8 6 139 0 0 5 4 Alkaline Phosphatase (U/L) Baseline 153 8 5 4 3 161 3 2 2 1 158 3 2 3 2 Alkaline Phosphatase Week 6 (U/L) (EOS) 136 8 6 2 2 137 4 3 1 1 137 5 4 2 2 Aspartate Aminotransferase (U/L) Baseline 153 0 0 4 3 161 0 0 1 1 158 0 0 2 1 Aspartate Aminotransferase Week 6 (U/L) (EOS) 136 0 0 5 4 138 0 0 3 2 139 0 0 3 2 Bilirubin (µmol/L) Baseline 153 0 0 1 1 161 0 0 0 0 158 0 0 2 1 Week 6 Bilirubin (µmol/L) (EOS) 136 0 0 0 0 138 0 0 1 1 139 0 0 1 1 Source: ad b.xpt; Software, R. Created by the Clinical Data Scientist. 1 Unscheduled visits are not included Reference ranges in patients ages 6 to 11 years: ALT, 5 to 30 U/L; AST, 0 to 47 U/L; a kaline phosphatase, 155 to 420 U/L; bilirubin, 2 to 21 µmol/L Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine Table 82. Out-of-Range Hepatobiliary Assessments (Study 812P302) SPN-812 ER 200 mg SPN-812 ER 400 mg Placebo (N=99) (N=105) (N=104) Parameter Visit N Low % High% NLow% High% N Low % High% Alanine Aminotransferase (U/L) Baseline 98 0 0 1 1 104 0 0 7 7 104 0 0 9 9 Alanine Aminotransferase Week 6 (U/L) (EOS) 86 0 0 3 4 96 0 0 13 14 102 0 0 8 8 Alkaline Phosphatase (U/L) Baseline 98 23 24 0 0 103 18 18 0 0 104 18 17 0 0 Alkaline Phosphatase Week 6 (U/L) (EOS) 86 17 20 0 0 95 15 16 0 0 101 17 17 1 1 113 Integrated Review Template, version date 2019/10/16

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SPN-812 ER 200 mg SPN-812 ER 400 mg Placebo (N=99) (N=105) (N=104) Aspartate Aminotransferase (U/L) Baseline 98 0 0 1 1 104 0 0 1 1 104 0 0 2 2 Aspartate Aminotransferase Week 6 (U/L) (EOS) 86 0 0 1 1 96 0 0 2 2 102 0 0 0 0 Bilirubin (µmol/L) Baseline 98 0 0 5 5 104 0 0 1 1 104 0 0 5 5 Week 6 Bilirubin (µmol/L) (EOS) 86 0 0 3 4 96 0 0 1 1 102 0 0 5 5 Source: ad b.xpt; Software, R. Created by the Clinical Data Scientist. 1 Unscheduled visits are not included Reference ranges in patients ages 12 to 17 years: ALT, 5 to 20 U/L; AST, 0 to 41 U/L; alkaline phosphatase, 110 to 630 U/L; bilirubin, 2 to 21 µmol/L Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine Table 83. Out-of-Range Hepatobiliary Assessments (Study 812P303) SPN-812 ER 200 mg SPN-812 ER 400 mg Placebo (N=107) (N=100) (N=103) Parameter Visit N Low % High% N Low%High% N Low % High% Alanine Aminotransferase (U/L) Baseline 107 0 0 2 2 100 0 0 4 4 103 0 0 2 2 Alanine Aminotransferase Week 8 (U/L) (EOS) 97 0 0 1 1 81 0 0 4 5 92 0 0 2 2 Alkaline Phosphatase (U/L) Baseline 107 5 5 2 2 100 4 4 2 2 103 4 4 0 0 Alkaline Week 8 Phosphatase (U/L) (EOS) 97 6 6 2 2 81 2 3 1 1 92 4 4 0 0 Aspartate Aminotransferase (U/L) Baseline 107 0 0 1 1 100 0 0 1 1 103 0 0 1 1 Aspartate Aminotransferase Week 8 (U/L) (EOS) 97 0 0 3 3 81 0 0 2 3 92 0 0 1 1 Bilirubin (µmol/L) Baseline 107 0 0 0 0 100 0 0 0 0 103 0 0 0 0 Week 8 Bilirubin (µmol/L) (EOS) 97 0 0 0 0 81 0 0 1 1 92 0 0 1 1 Source: ad b.xpt; Software, R. Created by the Clinical Data Scientist. 1 Unscheduled visits are not included Reference ranges in patients ages 6 to 11 years: ALT, 5 to 30 U/L; AST, 0 to 47 U/L; a kaline phosphatase, 155 to 420 U/L; bilirubin, 2 to 21 µmol/L Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine Table 84. Out-of-Range Hepatobiliary Assessments (Study 812P304) SPN-812 ER 400 mg SPN-812 ER 600 mg Placebo (N=100) (N=99) (N=97) Parameter Visit N Low % High% NLow%High% N Low % High% Alanine Aminotransferase (U/L) Baseline 100 0 0 8 8 99 0 0 4 4 97 0 0 6 6 Alanine Aminotransferase Week 7 (U/L) (EOS) 86 0 0 12 14 88 0 0 10 11 88 0 0 4 5

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SPN-812 ER 400 mg SPN-812 ER 600 mg Placebo (N=100) (N=99) (N=97) Alkaline Phosphatase (U/L) Baseline 100 18 18 0 0 99 16 16 0 0 97 21 22 1 1 Alkaline Phosphatase Week 7 (U/L) (EOS) 86 16 19 1 1 88 15 17 0 0 88 19 22 0 0 Aspartate Aminotransferase (U/L) Baseline 100 0 0 1 1 99 0 0 0 0 97 0 0 0 0 Aspartate Aminotransferase Week 7 (U/L) (EOS) 86 0 0 6 7 88 0 0 2 2 88 0 0 0 0 Bilirubin (µmol/L) Baseline 100 0 0 2 2 99 0 0 3 3 97 0 0 1 1 Week 7 Bilirubin (µmol/L) (EOS) 86 0 0 0 0 88 0 0 1 1 88 0 0 3 3 Source: ad b.xpt; Software, R. Created by the Clinical Data Scientist. 1 Unscheduled visits are not included Reference ranges in patients ages 12 to 17 years: ALT, 5 to 20 U/L; AST 0 to 41 U/L; alkaline phosphatase, 110 to 630 U/L; bilirubin, 2 to 21 µmol/L. Abbreviations: EOS = end of study; ER = extended release; SPN = viloxazine No patients receiving viloxazine ER in the development program met the criteria for drug-induced liver injury (increases >3-fold the ULN for AST or ALT with a total bilirubin level of >2-fold the ULN and an alkaline phosphatase level of <2-fold the ULN). Patients receiving viloxazine ER in the controlled phase 3 clinical studies were more likely to experience a shift in liver transaminases from within the reference range to greater than the upper limit of the reference range (Table 37). However, elevation of liver transaminases ≥3-fold the ULN occurred rarely in the phase 3 clinical trials. An 8-year-old male patient (301-18-1001) in Study 812P301 had baseline ALT and AST levels within the reference range but an ALT of >3-fold the ULN and an AST of >5-fold the ULN at the EOS visit. However, the EOS visit was conducted 118 days after the last intake of study medication (the patient was lost to follow up during this period) and the investigator assessed the liver transaminase elevations to be unlikely related to viloxazine ER. Table 85 (provided by the Applicant) provides an overview of patients who had marked elevations in liver transaminase, bilirubin, and alkaline phosphatase levels in the phase 2 and phase 3 controlled studies. Overall, these elevations were uncommon and did not appear to be dose-related.

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Table 85. Number of Subjects with Abnormal Liver Enzymes and Liver Function Tests (Studies 812P202, 812P301, 812P302, 812P303, and 812P304)

Source: Applicant’s Integrated Summary of Safety, Table 45, pages 100–101

Postmarketing Data

A review of the FAERS database conducted by the Division of Pharmacovigilance identified 4 reports of liver injury possibly associated with the previously marketed, immediate-release formulation of viloxazine.  3680944: 76-year-old male with a medical history of prostate cancer who was hospitalized for stroke. He had been prescribed clopidogrel for one month, carbamazepine for one year and one month, viloxazine for one year and two months, gonadorelin for two years, and bicalutamide for two years. On admission, laboratory tests showed hepatocellular damage. Abdominal ultrasound was unremarkable and HIV and cytomegalovirus (CMV) serologies were negative. All drugs were discontinued, and laboratory tests normalized within one week. All prescribed medications were considered possible causes of liver injury.

 3805941: Female patient (age unknown) hospitalized for hepatitis. The patient was prescribed irbesartan, viloxazine, zolpidem, , atorvastatin, and paracetamol.

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Hepatic ultrasound was within normal limits and hepatitis A, B, C, and HIV serologies were negative. The event was assessed as possibly related to irbesartan.

 3916193: 82-year-old female patient who developed fulminant hepatitis. The patient had a medical history of Horton’s disease, hypertension, cardiac insufficiency, depression, and atrial fibrillation. The patient received viloxazine ER from (b) (6) . was started on (b) (6) . Other concomitant medications included fluindione, prednisone, metoprolol, acenocoumarol, alprazolam, and . The hepatitis event occurred on (b) (6) . The patient presented to the hospital with tachycardia and atrial fibrillation. Laboratory investigations revealed elevated AST, ALT, and prothrombin levels. Abdominal ultrasound revealed a lithiastic gall bladder and moderate distention of the bile duct. The patient fully recovered. The possibility of hepatitis due to citalopram or viloxazine was considered, as was acute hepatic ischemia.

 4078413: 80-year-old male with a medical history of hyperthyroidism who was hospitalized for a general physical health condition that was associated with a decrease in weight. The patient was prescribed flecainide, viloxazine, clopidogrel, spironolactone, and furosemide. On admission, the laboratory assessments were remarkable for increased levels of gamma glutamyltransferase, alkaline phosphatase, and liver transaminases. The prescribed medications were discontinued, and the patient recovered. Although the possibility of liver injury associated with viloxazine ER in the FAERS cases cannot be ruled out, the cases are confounded by the presence of other medications and underlying medical conditions. The EudraVigilance database also includes reports of Hepatobiliary Disorders, including cholestasis, hepatitis, hepatitis cholestatic, hepatitis toxic, hepatocellular injury, and hyperbilirubinemia. Two of the reported cases of hepatitis were fatal. Vigibase contains 53 reports of hepatobiliary adverse reactions. EudraVigilance and Vigibase may contain duplicate reports, so it is not clear how many unique cases are represented in these databases. Additional clinical information about the case reports, including concomitant medical conditions and concurrent medications, was not available. The list of adverse reactions associated with immediate-release viloxazine ER in European labeling includes elevations of transaminases but no other references to liver injury.

Conclusion

Adverse events in the Hepatobiliary SOC were not reported in the controlled trials of viloxazine ER. The laboratory data from the controlled clinical trials indicate that patients receiving viloxazine ER may be more likely to experience clinically meaningful increases in liver transaminases. However, no case of drug-induced liver injury was identified, and most transaminase elevations were moderate (i.e., elevations <3-fold the ULN). Hepatic injury in the context of exposure to immediate-release viloxazine has been reported in postmarketing databases. In the cases for which clinical information is available, the reports are confounded by other medications and medical conditions that could have plausibly contributed to the liver injury. Of note, no case of severe liver injury was observed in the clinical trials for atomoxetine (which is mechanistically similar to viloxazine ER), but severe liver injury associated with

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atomoxetine has been reported in the postmarketing period. The currently available data do not establish that viloxazine ER is associated with hepatotoxicity. No labeling or other regulatory actions are indicated at this time. However, routine postmarketing surveillance for adverse reactions may provide additional information on a potential risk of liver injury with viloxazine exposure over time. 8. Therapeutic Individualization 8.1. Intrinsic Factors

Renal Impairment

The AUC of viloxazine increases by ~90% after administration to patients with severe renal impairment (estimated glomerular filtration rate [eGFR] ≤30 mL/min/1.73 m2, MDRD) without dialysis. In severely renal-impaired patients, the dose is recommended to not exceed 200 mg. Dosage adjustment is not recommended for patients with mild or moderate renal impairment.

Hepatic Impairment

Viloxazine ER is not recommended to be administered to patients with hepatic impairment because the effect in these patients has not been studied.

Other Intrinsic Factors

The primary cytochrome P450 (CYP) enzyme responsible for metabolism of viloxazine is CYP2D6. There is no clinically relevant difference in exposure between CYP2D6 poor (PM) and extensive (EM) metabolizers. Dose adjustment is not recommended. Based on the population pharmacokinetic (PK) analysis, gender and race do not exert a clinically significant effect. Therefore, dose adjustment according to gender or race is not recommended. Based on the population PK analysis, a decrease in weight results in an increase in exposure. Pediatric patients ages 6 to 11 years exhibited a 40% to 50% increase in exposure compared to those ages 12 to 17 years. The effects of intrinsic factors on viloxazine are presented in Figure 24.

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Figure 24. Effects of Intrinsic Factors on Viloxazine

Source: Reviewer’s analysis Abbreviations: AUC = area under the curve; RI = renal impairment 8.2. Drug Interactions Viloxazine increases the AUC of caffeine (a sensitive CYP1A2 substrate) by up to 5-fold. Therefore, viloxazine ER should be contraindicated in patients taking sensitive CYP1A2 substrates or CYP1A2 substrates with a narrow therapeutic range (e.g., , caffeine, doluxetine, ramelteon, tasimelteon, tizanidine, theophylline). The effect of viloxazine on moderately sensitive CYP1A2 substrates has not to date been evaluated. Coadministration of viloxazine with moderately sensitive CYP1A2 substrates is not recommended; indeed, dose reduction may be warranted (e.g., , pirfenidone). Refer to the full prescribing information for details on concomitant use of these drugs with strong CYP1A2 inhibitors. There is no clinically significant interaction between viloxazine and d-amphetamine or methylphenidate. The effects of viloxazine on other drugs are presented in Figure 25. Additionally, the effects of d-amphetamine and methylphenidate on viloxazine are outlined in Figure 26.

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Figure 25. Effect of Viloxazine on Other Drugs

Source: Reviewer’s analysis Abbreviations: AUC = area under the curve Figure 26. Effects of d-Amphetamine and Methylphenidate on Viloxazine

Source: Reviewer’s analysis Abbreviations: AUC = area under the curve; d-AMP = amphetamine; MPH = methylphenidate; VLX = viloxazine 8.3. Plans for Pediatric Drug Development The viloxazine ER development program has evaluated safety and efficacy in pediatric patients 6 to 17 years of age. At the July 28, 2017 end-of-phase 2 meeting, the Agency agreed that pediatric patients ages 4 to 5 years could be studied in the postmarketing period. The agreed Initial Pediatric Study Plan includes a waiver of the requirement for studies in pediatric patients under age 4 years and a deferral of a safety and efficacy study in pediatric patients ages 4 to <6 years. The Applicant has also committed to a 6-month, open-label safety study in patients 4 to <6 years of age. The Applicant plans to conduct a phase 3 study to evaluate the safety and efficacy of viloxazine ER 100 mg in patients ages 4 to 5 years of age with ADHD (Study 812P401). The Applicant has submitted the draft protocol as IND 108864. Patients who complete this study will be eligible to enter the open-label safety extension (812P310). Use of medications approved for ADHD is anticipated in pediatric patients ages 4 to 5 years. The review team therefore recommends that the completion of a safety and efficacy study and a long-term safety study in

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patients 4 to <6 years of age should be a postmarketing safety requirement under the Pediatric Research Equity Act.

Juvenile Animal Studies

Viloxazine was administered orally to juvenile rats from postnatal day (PND) 23 to 79 at doses of 43, 130, and 217 mg/kg/day, which are approximately 1-, 2-, and 3-fold, respectively, the MRHD of 400 mg based on mg/m2 in children. Viloxazine at 217 mg/kg/day decreased body weight, weight gain, and food consumption in both sexes. Sexual maturation, reproductive capacity, and learning and memory were not affected. The NOAEL for juvenile toxicity is 130 mg/kg/day, which is approximately 2-fold the MRHD based on mg/m2 in children. 8.4. Pregnancy and Lactation

Embryofetal Developmental Toxicity

Viloxazine was administered orally to pregnant rats during the period of organogenesis at doses of 13, 33, and 82 mg/kg/day, which are less than, equal to, and 2-fold, respectively, the MRHD of 400 mg based on mg/m2. Viloxazine did not cause maternal toxicity at doses up to 82 mg/kg/day. However, at a dose of 82 mg/kg/day, viloxazine increased early and late resorptions, delayed fetal development, and caused low incidences of fetal malformations or anomalies (craniorachischisis, missing cervical vertebrae, and morphological changes associated with hydranencephaly). The NOAEL for fetal toxicity and malformation is 33 mg/kg/day, which is approximately equal to the MRHD, based on mg/m2. Viloxazine was administered orally to pregnant rabbits during the period of organogenesis at doses of 43, 87, and 130 mg/kg/day, which are approximately 4-, 7-, and 11-fold, respectively, the MRHD of 400 mg based on mg/m2. Viloxazine decreased maternal body weight, weight gain, and food consumption at doses ≥87 mg/kg/day but did not cause fetal toxicity at doses up to 130 mg/kg/day. The NOAELs for maternal and fetal toxicity are 43 and 130 mg/kg/day, respectively, which are approximately 4- and 11-fold, respectively. the MRHD based on mg/m2.

Pre- and Postnatal Developmental Toxicity

Viloxazine was administered orally to pregnant rats during gestation and lactation at doses of 43, 87, and 217 mg/kg/day, which are approximately 1-, 2-, and 5-fold, respectively, the MRHD of 400 mg, based on mg/m2. Viloxazine caused maternal toxicity of decreased body weight, weight gain, and food consumption at doses ≥87 mg/kg/day and maternal death at 217 mg/kg/day. At these maternally toxic doses, viloxazine reduced the rate of live birth, decreased viability, and delayed growth and sexual maturation without affecting learning and memory in the offspring. The NOAEL for maternal and developmental toxicity is 43 mg/kg/day, which is approximately equal to the MRHD, based on mg/m2. Viloxazine was administered orally to pregnant mice during gestation and lactation at doses of 13, 33, and 82 mg/kg/day, which are approximately less than, equal to, and 2-fold the MRHD of 400 mg, respectively, based on mg/m2. Viloxazine at 82 mg/kg/day during the gestation period caused maternal death and decreased body weight in the offspring. The NOAEL for both

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maternal and developmental toxicity is 33 mg/kg/day, which is less than the MRHD, based on mg/m2. Although no direct measurement of viloxazine concentration in milk was conducted, circulating viloxazine was present in rat pups as early as PND 4; therefore, viloxazine is likely present in rat milk. It should be noted that in both rat and mouse, administration of viloxazine during the late gestation period caused maternal death at doses equal to or less than the MRHD based on mg/m2 (mouse) or the AUC (rat). Therefore, dosing of viloxazine during pregnancy is not recommended from a nonclinical perspective. See the full review in DARRTS: Date 22 June 2020; Ref ID, 4629249 by Catherine Roca, MD and Miriam Dinatale DO of the Division of Pediatric and Maternal Health. The clinical data are inadequate to fully characterize the risks from viloxazine during pregnancy and lactation. Therefore, postmarketing requirements (PMRs) for a single-arm pregnancy study and a milk-only lactation study for viloxazine will be issued to the Applicant. Labeling recommendations were made by the Division of Pediatrics and Maternal Health (DPMH).

Pregnancy

Despite several decades of use as an antidepressant in several European countries, clinical data related to viloxazine are limited to approximately 25 cases and are inadequate to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There were no reports of maternal death in any of these cases. Given the unexplained maternal deaths in the nonclinical data and the availability of alternative treatments for ADHD, DPMH recommends that viloxazine be discontinued when pregnancy is recognized unless the benefits of therapy outweigh the potential risk to the mother. The previous lack of use in pregnant populations and labeling recommendation that discourages use during pregnancy make recruitment of a sufficient number of exposed pregnancies for a pregnancy registry unlikely. Therefore, a single-arm pregnancy safety study is recommended to evaluate the effect of viloxazine on pregnancy outcomes.

Lactation

There are no data available on the presence of viloxazine in human milk or on its effect on the breastfed infant or on lactation. Because there is a possibility that viloxazine will be used in females of reproductive potential, DPMH recommends that a milk-only (no infant exposure) study be performed to determine if viloxazine is present in breast milk.

Females and Males of Reproductive Potential

There are no human data on the effect of viloxazine on fertility. Animal studies did not demonstrate an adverse effect on fertility; therefore, Subsection 8.3 will not be included in the labeling.

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9. Product Quality 9.1. Device or Combination Product Considerations Not applicable. 10. Human Subjects Protections/Clinical Site and Other GCP Inspections/Financial Disclosure

No financial disclosure concerns with the potential to influence the interpretation of safety or efficacy were uncovered. Inspections were requested of the study sites (which enrolled a large number of patients relative to other sites) listed in Table 86. The Office of Scientific Investigations (OSI) identified one study site (Dr. Lopez-Brignoni) where there were dosing irregularities. OSI recommended that the Division consider excluding the data from this site from the per-protocol analysis. The Division included these data (in keeping with the randomization principle), but conducted a sensitivity analysis that determined that the data from this site did not change the overall study results. Please see the OSI consultative review for full details of the inspection results. Table 86. Clinical Site Inspections (Studies 812P301, 812P302, 812P303, and 812P304) Number Protocol of Site ID Subjects Study Title Evaluation of SPN-812 ER 100 and 200 mg Efficacy and Safety 812P301 53 in Children with ADHD - A Double-Blind, Placebo- Site 006 Controlled, Pivotal Trial Robert Bond Molpus, MD Evaluation of SPN-812 ER 200 and 400 mg Efficacy and Safety 812P302 28 in Adolescents with ADHD - A Double-Blind, Placebo- Controlled, Pivotal Trial Evaluation of SPN-812 ER 200 Site 108 and 400 mg Efficacy and Safety James E. Cain, MD 812P302 23 in Adolescents with ADHD - A Double-Blind, Placebo- Controlled, Pivotal Trial Evaluation of SPN-812 ER 200 and 400 mg Efficacy and Safety Site 121 812P302 14 in Adolescents with ADHD - A Evelyn Lopez-Brignoni, MD Double-Blind, Placebo- Controlled, Pivotal Trial

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Number Protocol of Site ID Subjects Study Title Evaluation of SPN-812 ER 200 and 400 mg Efficacy and Safety 812P303 33 in Children with ADHD - A Double-Blind, Placebo- Site 9 Controlled, Pivotal Trial Andrea Marraffino, PhD Evaluation of SPN-812 ER 400 and 600 mg Efficacy and Safety 812P304 31 in Adolescents with ADHD - A Double-Blind, Placebo- Controlled, Pivotal Trial

Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; SPN = viloxazine 11. Advisory Committee Summary

Not applicable.

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III. Appendices

12. Summary of Regulatory History

The Agency has had interactions with the Applicant since the pre-IND stage. The Applicant has participated in a pre-IND meeting, end-of-phase 2 meeting, and pre-NDA meeting. The Agency has also provided guidance regarding the pediatric study plan and the assessment of QT interval effects. During the March 2010 pre-IND meeting, the Agency advised the Applicant about required carcinogenicity studies as well as pharmacokinetic and other clinical pharmacology studies. The Agency also provided guidance about the development of a modified release form. The Applicant submitted a 2009 consultation report that investigated the reasons for viloxazine’s withdrawal from the European market and confirmed that the drug was not withdrawn because of concerns over safety (Contracted Research Results to Determine Regulatory Status of Viloxazine in Selected European Countries, Module 1.13.10). A second pre-IND meeting was held in June 2013. The Applicant had been previously advised that a laboratory classroom study would be necessary; during this meeting, the Agency clarified that in-classroom testing would no longer be required. The Agency agreed that that the ADHD Rating Scale–IV (ADHD-RS-IV) would be acceptable as a primary endpoint in efficacy studies. The Applicant also indicated that that the Clinical Global Impression-Improvement (CGI-I) scale would serve as a secondary endpoint. However, the Agency did not offer an opinion about the appropriateness of the CGI-I as an endpoint at that time. The Applicant submitted the IND on June 2015, under which the studies were allowed to proceed beginning in July 2015. The Agency provided further guidance on the phase 3 development program during an end-of- phase 2 meeting held in July 2017. The Agency agreed that safety and efficacy in patients ages 4 to 6 years could be evaluated in the postmarketing setting. The Agency also agreed that an updated version of the ADHD Rating Scale, the ADHD-RS-5, would be an appropriate primary endpoint in the phase 3 efficacy and safety studies. Although the Agency had previously advised that evaluations for ophthalmologic changes and urinary retention would be required because of warnings contained in the French labeling for viloxazine, the Applicant pointed out that the warnings were based on theoretical concerns and not on human safety findings. The Agency subsequently agreed that ophthalmologic and urinary tract evaluations would not be needed. The Agency recommended CYP2D6 genotyping in the phase 3 clinical trials and a total QT study. The Applicant additionally agreed to conduct a study to assess the PK of viloxazine ER in patients with renal impairment. The Agency agreed that nonclinical and clinical abuse potential studies were not necessary but advised that the Applicant monitor for abuse-related events. The Agency discussed the ICH E1 guideline for long-term exposure (The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for the Long-Term Treatment of Non- Life-Threatening Conditions), which recommends a minimum total exposure of 1000 to 1500

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patients, with at least 300 patients exposed for 6 months and 100 patients exposed for 12 months at the relevant doses. The Agency noted that convulsions had occurred in multiple species in nonclinical studies. The Agency expressed concern over the lack of a safety margin between the no observed adverse effect level (NOAEL) exposures for seizures in animals and the blood levels already attained in clinical trials. After the meeting the Applicant submitted published literature on the clinical safety of viloxazine. The information in the document was derived from a literature search for relevant clinical studies and case reports. One of the included studies reviewed 120 viloxazine clinical trials and calculated the incidence of seizures associated with viloxazine treatment to be 0.01% (Edwards and Glen-Bott 1984). The Agency agreed after review of the submitted data that there did not appear to be a clear seizure risk associated with viloxazine in humans. A pre-NDA meeting was held in July 2019, during which the Agency agreed that the completed clinical and nonclinical studies could support NDA filing. The Agency also agreed that the completed reproductive studies and the analysis of the metabolic profile were acceptable for filing. The Applicant confirmed that the final to-be-marketed formulation was used in key efficacy and clinical pharmacology studies. The Agency advised that a phototoxicity study should be completed and that a drug-drug interaction study with a strong CYP2D6 inhibitor may be required. The Agency expressed concern about the lack of a hepatic impairment study but after the meeting agreed that this study could be deferred (b) (4) . The Agency also expressed reservations about the use of the CGI-I as a key secondary endpoint in the phase 3 trials because of its susceptibility to recall bias. The Agreed Pediatric Study Plan was submitted in January 2019 and includes a waiver for children under the age of 4 years and deferral of one safety and efficacy study in children ages 4 to <6 years. In October 2019, the Agency advised that Applicant’s completed assessments of QT interval effects were adequate for NDA submission. The Applicant submitted the 505(b)(1) NDA on November 8, 2019.

13. Pharmacology Toxicology: Assessments and Additional Information 13.1. Summary Review of Studies Submitted Under IND All nonclinical studies were reviewed under the NDA (see Section 13.2).

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proposed limits are consistent with the ICH M(7) guideline and are adequate from a nonclinical safety perspective. Other nonmutagenic impurities are controlled per ICH Q3(A)&(B) guidance. 13.2.1.2. Excipients There are no novel excipients of safety concern in the drug product. The excipients are either compendial (USP or NF monograph), controlled at levels lower than those in the FDA inactive ingredient database, or generally recognized as safe. 13.2.2. Pharmacology 13.2.2.1. Primary Pharmacology The Applicant conducted multiple in vitro screening assays (Studies 809V-Tox2007-001a and - 001b, and 809V-Tox2007-019-101027606) to investigate the binding of viloxazine to various receptors, transporters, and enzymes. Racemic viloxazine4 at concentrations up to 10 µM showed binding affinity for the adrenergic β2, 5-HT1A, 5-HT1B, 5-HT2B, 5-HT2C, and 5-HT7 receptors and the norepinephrine transporter (NET) with Ki values of 1.1, 4.5, 2.3, 3.9, 6.4, 1.2, and 0.63 µM 5, respectively. At 100µM, viloxazine showed weak binding to a large number of enzymes and receptors (Study 812V-Pharm2018-035); however, given that the expected maximum plasma concentration (Cmax) at the maximum recommended human dose (MRHD) of 400 mg is about 3.9 µg/mL (~16µM) or 0.78 µg/mL (~ 3µM) when adjusted for 80% protein binding, the clinical relevance of binding at such a high concentration appears limited. In another in vitro assay (812V-Tox2016-027), 5-hydroxyviloxazine, a human metabolite of viloxazine, showed binding affinity for the MT3 (melatonin receptor 3), 5-HT2B, 5-HT2c, and 5-HT3 receptors; the NET; and the COX2 enzyme (66.4%, 54%, 82.5%, 54.1%, 96.9%, and 50.9% binding at 10µM, respectively). In assays to differentiate the binding affinity of viloxazine isomers (Studies 809V-Tox2007-043, -044, and -051), R(+)- and S(-)-viloxazine generally showed similar binding profiles. Specifically, at 10µM, both R(+)- and S(-)-viloxazine showed binding affinity for the β2, 5-HT2B receptors, CYP1A2, and NET, with S(-)-viloxazine showing higher affinity for NET (Ki 0.09µM) relative to R(+)-viloxazine (Ki 1.9µM). In addition, R(+)- and S(-)-viloxazine showed binding affinity for the β1 and 5-HT2C receptors, respectively. None (R(+)-, or S(-)- viloxazine, or the ) showed significant binding affinity for the neuronal α4β2 or α7 nicotinic receptors (Study 809V-Tox2008-007). In follow-up in vitro functional assays (Studies 809V-Tox2007-001c and 812V-Pharm2019- 001), racemic viloxazine inhibited norepinephrine (NE) uptake with a half maximal inhibitory concentration (IC50) of 0.2µM, suggesting that viloxazine is a norepinephrine reuptake inhibitor. However, when tested in vitro for serotonergic activity (Studies 812V-Tox2018-007 and 812V- Pharm2019-001), viloxazine showed both weak agonist and antagonist activity at the 5-HT2B receptor. In addition, viloxazine showed weak agonist activity at the 5-HT2C receptor and weak

4 Unless specified, viloxazine, when used alone in this review, stands for a racemic viloxazine mixture, whereas the R and S racemates are presented as R(+)-viloxazine and S(-)-viloxazine, respectively.

5 Individual Ki, IC50, or EC50 values of the same receptor may vary in different assays; however, they were generally in the same range; therefore, representative values from one study are presented.

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antagonist activity at the 5-HT1B, and 5-HT7 receptors (Table 87). The in vitro activities of R(+)-, S(-)-viloxazine, and the racemic mixture, were generally similar (Studies 809V-Tox2007-035, - 050, and SUP-2007-001a). In an ex vivo assay in the rat stomach fundus (Study 1-1027933-0), viloxazine at concentrations up to 30µM did not show any significant agonist or antagonist activity at the 5-HT2B receptor, relative to the reference compounds, α-methyl-5-HT (agonist) and SB206553 (antagonist). Given the inconsistent findings for the serotonin receptors, there is inadequate evidence to support a serotonergic mechanism of action for viloxazine. In male Sprague–Dawley rats (Studies 812V-Pharm2019-023 and 018), after a single intraperitoneal administration of 50 mg/kg, viloxazine increased the norepinephrine (NE), dopamine (DA), and serotonin (5-HT) levels in interstitial fluid collected from the prefrontal cortex, nucleus accumbens, and amygdala. Glutamate and gamma-aminobutyric acid levels were largely unaffected. The peak increases in the NE, DA, and 5-HT levels generally correlated with the Cmax/ time to maximum concentration (Tmax) of viloxazine, which were 12.7 µg/mL and 60 minutes, respectively (higher than the clinical Cmax of 3.9 µg/mL at the MRHD of 400 mg). In summary (Table 87), pharmacology studies showed that viloxazine inhibits NE reuptake and increases the brain NE level by inhibiting NET; however, the evidence is inadequate to support a clear drug effect on serotonin receptors. Table 87. Summary of the Pharmacological Activity of Viloxazine at Various Receptors and Transporters Target In Vitro Binding In Vitro Functional Assay1 Receptor (Ki, µM) Agonist Antagonist In Vivo NET 0.63 No activity Antagonist, IC50=0.2µM ↑NE, 5-HT, 5-HT1A 4.5 No activity Weak antagonist, and DA levels IC50=17.5µM in rat brain 5-HT1B 2.3 No activity weak antagonist, (pre-frontal IC50=18µM cortex, 5-HT2B 3.9 No activity or agonist No activity or weak nucleus EC50=1 µM antagonist, IC50=27µM accumbens, 5-HT2C 6.4 No activity or agonist No activity and amygdala) EC50=1.6 µM 5-HT7 1.2 No activity or weak Weak antagonist, agonist, EC50=32 µM IC50=100µM β2 1.1 No activity antagonist, IC50=10µM DAT2 >100 ND ND SERT2 17. 30 ND Negligible antagonist activity IC50=257µM Source: Modified/reformatted based on the data in the Applicant’s study reports 1 Depending on the assay, viloxazine showed inconsistent activity at various 5-HT receptors in functional assays, ranging from no activity to agonist and antagonist activity 2 Binding affinity data based on published literature (Tatsumi et al. 1997) Abbreviations: 5-HT = serotonin; DA = dopamine; ND = not determined due to minimal binding affinity at the transporter; NE = norepinephrine In addition to the studies described above, the Applicant also referred to several published studies (Greenwood 1975; Pinder et al. 1977) that discuss the in vivo pharmacologic effects of viloxazine. In animals, viloxazine, similar to tricyclic antidepressants and benzodiazepines, exhibited central nervous system (CNS) depressive effects, such as decreased body temperature and locomotor activity, and an elevated seizure threshold. However, in the nonclinical studies in the current NDA package, chronic administration of viloxazine was associated with an increased

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incidence of convulsions in multiple animal species. Therefore, the anticonvulsive activity of viloxazine is questionable. 13.2.2.2. Secondary Pharmacology No dedicated secondary pharmacology studies were submitted in this NDA. The off-target binding of viloxazine was investigated as part of the primary pharmacology program. Except for those discussed in the primary pharmacology section, viloxazine did not show significant binding to several receptors, transporters, and enzymes in in vitro screening assays. In addition, viloxazine, at concentrations up to 100µM, did not show significant activity on the voltage-gated calcium channel. However, viloxazine induced a dose-dependent increase in the inhibition of the sodium channel with an IC50 of 18µM (15.7%, 34.2%, and 82.9% inhibition at 1, 10, and 100µM, respectively) (Study 812V-Pharma2019-002). Viloxazine also weakly inhibited serotonin uptake with an IC50 of 257µM (Study 812V-Pharm2019-003). Because the clinical Cmax is less than 20µM, viloxazine at clinically relevant levels exerts a negligible serotonergic effect via SERT inhibition. 13.2.2.3. Safety Pharmacology 13.2.2.3.1. Central Nervous System In Sprague-Dawley rats, after a single oral dose at 0 (control vehicle, water), 25, 100, and 400 mg/kg (n=5/sex/group, Study 809V-2007-022, GLP), viloxazine-related CNS effects included mydriasis at ≥100 mg/kg; decreased body temperature at 400 mg/kg; and decreased approach response at 400 mg/kg. The pupillary and body temperature response is likely associated with the adrenergic pharmacology of the drug as an NE reuptake inhibitor (Simmonds and Iversen 1969), whereas the decreased approach response is likely due to mydriasis and decreased visual acuity, rather than a direct drug effect, because other tactile responses are not affected. The NOEL for CNS safety pharmacology is 25 mg/kg in rat. 13.2.2.3.2. Cardiovascular System

In vitro hERG Inhibition Assay

In an in vitro hERG assay (Study 809V-Tox2007-028, GLP), viloxazine dose-dependently inhibited hERG potassium currents with an IC50 value of 67.7µM. The percent inhibition was 8.6%, 28.4%, 59.7%, and 87.2% at 10, 30, 100, and 300µM viloxazine, respectively.

In Vivo Cardiovascular Safety Pharmacology Study

In telemetry-instrumented male conscious dogs (Study 809V-Tox2007-031, GLP), after a single oral dose (capsule) of viloxazine at 0 (control, empty capsule), 5, 25, and 50 mg/kg (n=4, Latin square design) there were no drug-related changes in ECG (PR, QRS, QT, or QTcF) or blood pressure (diastolic, systolic, or mean arterial pressure) parameters relative to controls. Heart rate was slightly decreased at all doses without a clear dose-response (decreases of 4%, 9%, and 5%, respectively); therefore, these effects are not considered to be adverse. The NOAEL for cardiovascular safety pharmacology is 50 mg/kg in dog.

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13.2.2.3.3. Respiratory System In male Sprague-Dawley rats (Study 809V-Tox2007-021, GLP), after a single oral dose of viloxazine at 0 (vehicle control, water), 25, 100, and 400 mg/kg (n=8/group), there were no drug- related changes in respiratory functions relative to controls. The NOEL for respiratory safety pharmacology is 400 mg/kg in rat. 13.2.3. Pharmacokinetics/ADME The bioanalytical methods are validated for determination of viloxazine in the plasma of rat, dog, mouse, and rabbit with a lower limit of quantitation of 1 ng/mL and a linearity range of 1 to 1000 ng/mL. The bioanalytical methods are validated for determination of R(+)-viloxazine and S(-)- viloxazine concentrations in the plasma of dog and rat with a lower limit of quantitation of 10 ng and a linearity range of 10 to 10,000 ng/mL. 13.2.3.1. Absorption and Distribution The pharmacokinetic profile after a single oral dose of [14C]-viloxazine at 100 mg/kg (150 µCi/kg) was investigated in male and female Sprague Dawley (albino) rats and male Long– Evans (partially pigmented) rats (Study 809V-Tox2007-023, GLP). After oral administration to Sprague-Dawley rats, viloxazine was rapidly absorbed in both sexes. The blood and plasma radioactivity concentrations peaked (Tmax) at 1 or 2 hours postdose and was eliminated relatively rapidly from plasma with a terminal half-life (T1/2) of ~3.5 hours. Radioactivity primarily partitioned in the plasma with a blood-to-plasma ratio of ~0.6, suggesting limited binding or partitioning into red blood cells. The majority of radioactivity (~89%) was excreted within 24 hours, with urine as the primary route of elimination, followed by feces (~6%). After oral administration to partially pigmented Long–Evans rats, viloxazine was rapidly and widely distributed to various tissues. In general, the tissue concentrations of radioactivity peaked at 1 or 2 hours postdose and were mostly eliminated by 24 hours postdose. High concentrations of radioactivity were found in tissues/organs along the gastrointestinal (GI) and urinary tracts, whereas lower radioactivity was observed in the muscle, eye lens, bone, testis, and abdominal fat. CNS tissues had very low radioactivity, which was not detected by 8 hours postdose. In pigmented tissues, the radioactivity concentration was relatively high in the uveal tract, peaking at 2 hours postdose and rapidly declined thereafter. The radioactivity concentration in the skin was generally low. These data suggest that viloxazine or its metabolites do not preferentially distribute to or accumulate in the skin; viloxazine and its metabolites reversibly bind to melanin in the uveal tract but are rapidly dissociated or eliminated. In an in vitro plasma protein-binding assay (Study 809V-Tox2007-026, GLP), viloxazine at concentrations up to 10 µg/mL showed moderate protein binding in plasma samples from human (75.7% to 82.2% bound), rat (50.2% to 56% bound), and dog (40.8% to 48.8% bound, Table 88). In all species, the percentage of viloxazine bound to plasma proteins decreased with increasing drug concentration, suggesting potential saturation at high concentrations.

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Table 88. In Vitro Plasma Protein Binding of Viloxazine in Human, Rat, and Dog Species/Concentration Percent Bound (µg/mL) 0.5 1 3 10 Human 82.2 81.4 79.5 75.7 Dog 48.8 48.0 46.1 40.8 Rat 56.0 55.4 54.0 50.2 Source: Modified/reformatted based on the data in the Applicant’s study reports When incubated with human blood samples (Study 812V-Tox2018-030, GLP), viloxazine at clinically relevant concentrations (approximately 0.1-, 1-, and 10-fold the clinical Cmax) did not preferentially bind to or accumulate in blood cells (blood-to-plasma ratio 0.42 to 0.88). Therefore, plasma is an appropriate biological matrix for PK and TK measurements. 13.2.3.2. Metabolism and Excretion

In Vitro Metabolism

The in vitro metabolism of [14C]-viloxazine was investigated in primary hepatocytes derived from rat (male), dog (male), and human (male) (Study 809V-Tox2007-027, non-GLP). There were significant species differences in the in vitro metabolic profile, which were confirmed by in vivo studies. Viloxazine was extensively metabolized in rat hepatocytes (>90%) with 11 metabolites identified, moderately metabolized in dog hepatocytes (~50%) with 9 metabolites identified, and minimally metabolized in human hepatocytes (<10%) with 4 metabolites identified (Table 89). Two rat-specific metabolites (U1, unknown and M5, desethyl-viloxazine) and 1 dog-specific metabolite (M 10, methyl-viloxazine) were identified. However, despite the difference in metabolism, there were no unique human metabolites. Table 89. In Vitro Metabolites of [14C]-Viloxazine Formed in Rat, Dog, and Human Hepatocytes after a 120-Minute Incubation

Source: Excerpted from the Applicant’s study reports. Abbreviations: SPN = viloxazine

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Similar to the results from human hepatocytes, limited metabolic conversion of [14C]-viloxazine was observed in pooled human hepatic microsomes (Study 809V-Tox2007-032). In subsequent assays using CYP-specific inhibitory antibodies or selective inhibitors, it was shown that multiple CYP enzymes were involved in the in vitro metabolism of viloxazine in human hepatic microsomes or in supersomes expressing recombinant human CYP enzymes (CYP2D6, CYP1A2, CYP2B6, and CYP3A4).

In Vivo Metabolism and Excretion

In rat, after oral administration (Study 809V-Tox2007-023, GLP), viloxazine is extensively metabolized. The primary metabolic conversion is O-dealkylation followed by sulfation or glucuronidation. Other metabolic pathways include hydroxylation of the phenyl ring, and hydroxylation and oxidation of the ring (Figure 27). In plasma, the primary metabolite is desethyl viloxazine (M5); at 1 hour postdose, it accounted for 60.2% and 45.6% of the total radioactivity in males and females, respectively, whereas the parent drug accounted for only ~9.17% and 21.7%, respectively. Similarly, in urine, desethyl viloxazine is the primary metabolite, accounting for 67.7% and 51.1% of the radioactivity in males and females, respectively. In feces, hydroxylated metabolites of viloxazine were the most abundant metabolites, accounting for ~18% of the radioactivity; the unchanged parent drug accounted for ~13% of the radioactivity in both males and females. Compared to rat, the in vitro and in vivo metabolism of viloxazine in human is limited. In human liver microsomes and in supersomes expressing human CYP2D6 (Study 812V-Tox2018-023), 5-hydroxyviloxazine was generated as the main metabolite, which was further conjugated into glucuronidated-5-hydroxyviloxazine in the presence of UGT1A9 and UGT2B15, but not UGT1A1, UGT1A3, UGT1A4, UGT1A6, or UGT2B7 (Study 812V-Tox2017-001). In human, the major circulating drug-related components in plasma are glucuronidated 5-hydroxy- viloxazine (P1, which corresponds to metabolites M1/M2 in rat) and unchanged viloxazine (P2). In addition, unconjugated 4 and 5-monohydroxylated viloxazine (U2), as well as glucuronidated N-carboxylated-viloxazine (U4) were detected as minor metabolites in plasma (Table 90). In urine, there were four major components: glucuronidated 5-hydroxy-viloxazine, 5-hydroxy- viloxazine, unchanged viloxazine, and glucuronidated N-carboxylated-viloxazine.

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Figure 27. Metabolic Conversion of Viloxazine in Rat

Source: Excerpted from the Applicant’s study reports Abbreviations: SPN = viloxazine

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Table 91. Relative Levels of Glucuronidated 5-Hydroxy-Viloxazine in Human and Rat

Source: Excerpted from the Applicant’s study reports Rat exposure data were from Study 809V-Tox207-023; human exposure data were from the mass-balance Study 812p111 Both 5-hydroxyviloxazine and glucuronidated 5-hydroxyviloxazine were found to rapidly penetrate the mouse brain after a single IV viloxazine dose of 5 mg/kg, with Tmax values of 1 and 0.5 hours, respectively (Study 812-Tox2018-020). 13.2.3.3. Drug-Drug Interactions The inhibition or induction potential of viloxazine against CYP enzymes and transporters was investigated in multiple in vitro studies. In pooled human liver microsomes (Study 809V-Tox2007-008), viloxazine at concentrations up to 100 µg/mL did not significantly inhibit CYP2B6, CYP2C8, CYP2C9, or CYP2C19. However, viloxazine competitively inhibited CYP1A2, CYP2D6, and CYP3A4 with IC50 values of 0.535, 54.6, and 65.2 µg/mL, respectively, and Ki values of 0.124, 12.7, and 26.8 µg/mL, respectively. The inhibition was not NADPH dependent. In another in vitro assay using pooled liver microsomes (Study 812V-Tox2018-024), viloxazine did not inhibit CYP2C8, CYP2C9, or CYP2C19. Viloxazine reversibly inhibited CYP1A2, CYP2B6, CYP2D6, and CYP3A4/5 with IC50 values of 0.269, 184, 141, and 221µM, respectively. In primary human hepatocyte cultures (Study 809V-Tox2007-009), viloxazine at 2 µg/mL induced CYPA1A1/2 in 2 of 3 hepatocyte cultures. At 20 µg/mL, viloxazine induced CYP2C9, CYP1A2, and CYP2B6 in 1, 2, and 3 of 3 hepatocyte cultures, respectively. No enzyme induction was observed at 0.2 µg/mL. No CYP3A4/5 induction was observed at concentrations up to 20 µg/mL. In another set of assays using a different batch of human hepatocytes (Study 812V-Tox2017-002), viloxazine significantly induced mRNA expression of CYP1A2 and CYP2B6 with EC50 values of 16.7 and 15.4 µg/mL, respectively; no induction of CYP3A4 was observed. In HEK293 cells expressing human OATP1B1*1a and OPAT1B3 transporters (Study 812V- Tox2018-025), viloxazine was not a substrate for OATP1B1*1a or OATP1B3. In cultures of MDCK and/or Caco-2 cells expressing human transporters of OAT1, OAT3, OCT2, OATPP1B1, OATP1B3, BCRP, and Pgp, viloxazine at 150µM did not inhibit OATP1B1, OATP1B3, or BCRP; but exerted a weak inhibitory effect on Pgp, OAT1, OAT3, and OCT2 (9.41%, 29.7%, 33.4%, and 43.9% inhibition, respectively). In a similar in vitro assay (Study 812V-Tox2018-026), viloxazine was a weak inhibitor of Pgp, BCRP, OATP1B1*1a, OATP1B3, and MATE1 with IC50 values of 1.5, 1.68, 1.84, 2.7, and 0.14mM, respectively. Viloxazine did not show any significant inhibition of MATE2-K at concentrations up to 3.3mM. Considering the clinical Cmax of ~20µM, the risk for viloxazine-related inhibition of these transporters appears to be limited from a nonclinical perspective.

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13.2.4. General Toxicology 13.2.4.1. Single-dose Toxicity In male Swiss–Webster mice (Study 723-0046, non-GLP), a single oral administration of viloxazine at ≥434 mg/kg caused ataxia, convulsions, and/or deaths. Ataxia and/or convulsions generally occurred within 5 minutes postdose and their severity increased dose dependently. The median lethal dose (LD50) and LD2 were estimated to be 694 and 290 mg/kg6, respectively. In male and female Wistar rats (Study 723-0016, non-GLP), a single oral dose of viloxazine at ≥487 mg/kg caused CNS depression, ataxia, labored respiration, convulsions, and/or deaths. The toxicities generally occurred within 10 minutes postdose, and their severity increased dose dependently. The LD50 was estimated to be 1413 and 1821 mg/kg in males and females, respectively. Similar dose-dependent toxicities of CNS depression, ataxia, labored respiration, hunched posture, and/or deaths were also observed in Sprague-Dawley rats when orally administered the same doses, although convulsions were not observed at doses up to 971 mg/kg7, suggesting strain-related differences in the convulsion threshold. The LD50 was estimated to be 1343 and 1179 mg/kg in males and females, respectively. 13.2.4.2. Repeat-dose Toxicity 13.2.4.2.1. Repeat-dose Toxicity Studies in Rat Study Title.: A 13-Week Oral Gavage Toxicity and Toxicokinetic Study of SPN-809V in Sprague Dawley Rats with a 4- Week Recovery Period Study no.: 809V-Tox2009-006 Study report location: EDR, SDN-1 Study initiation date: August 21, 2009 Conducting laboratory and location: (b) (4) Duration: 13 Duration Units: weeks GLP compliance: Y Drug, lot #, and % purity: Viloxazine; 080047 (CMLW-147/08-VL3); ~ 100% (100.2% based on HPLC) Target Organ+: LIVER

6 LD2 value was derived by extrapolation of the lower end of the LD50 curve.

7 At doses higher than 971 mg/kg, deaths occurred without any observation of convulsions.

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Key Findings

 Viloxazine at 217 mg/kg/day caused, in both sexes, hepatocellular hypertrophy and vacuolation in the liver, with correlative increases in the liver weight and the serum alkaline phosphatase level. These changes were reversible after recovery.  Females had higher drug exposure than males, which correlated with an increased incidence of histopathology findings in the liver.  Based on liver findings, the NOEL is considered to be 87 mg/kg/day. The corresponding exposures after 13 weeks of repeat treatments were 10,600 and 15,300 ng*hour/mL for males and females, respectively. Reviewer’s note: Findings in the liver are likely an adaptive response to drug treatment and not necessarily adverse. Therefore, the NOAEL could arguably be set at 217 mg/kg/day for the current study. However, in a subsequent rat carcinogenicity study, viloxazine at 217 mg/kg/day caused convulsions in multiple animals. Therefore, given the overall evidence, it is appropriate to set the NOAEL at 87 mg/kg/day. Table 92. Methods for A 13-Week Oral Gavage Toxicity and Toxicokinetic Study of SPN-809V in Sprague Dawley Rats with a 4-Week Recovery Period Methods Details Doses: 0 (vehicle control), 22 (LD), 87 (MD), and 217 (HD) mg/kg/day Frequency of dosing: Once daily Number/sex/group: Main study: n=10/sex/group Recovery: additional n=5/sex in control and HD only TK: n=9/sex/group for LD, MD, and HD and n=3/sex for control Dose volume: 10 mL/kg Formulation/vehicle: H2O Route of administration: ORAL GAVAGE Species: RATRATRAT Strain: SPRAGUE-DAWLEY Age/sexual maturity: Approximately 7–8 weeks of age at treatment initiation Comment on study design Dose selection was based on the 7-day and 4-week repeat dose and conduct: studies. At 433 mg/kg/day, viloxazine induced severe CNS toxicity of convulsion and excessive decreases in body weight and weigh gain, indicating that the MTD was exceeded. At 217 mg/kg/day, viloxazine caused tolerable decreases in body weight (↓up to ~9%) and weight gain (↓up to 19%) and no severe CNS adverse effects. Therefore, 217 mg/kg/day was selected as the high dose in the current study. Dosing solution analysis: The stability and concentration of the dosing formulation were confirmed to be acceptable. Source: summarized from the Applicant's study reports

Observations and Results

Mortality

There were no drug-related premature deaths in the study. One of 15 control males (No. 7758) was found dead on day 52 with no clear cause of death. One of 15 HDMs (No. 7705) was euthanized on day 13. The cause of death was hemorrhagic cystitis with inflammation in the urinary bladder. This single incidence in the HDM is not considered to be drug related because

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1) no similar finding was observed at this dose in the current study or at similar or higher doses in previous studies; and 2) existing knowledge of the pharmacology or toxicology of the drug does not provide a plausible mechanism for the hemorrhagic cystitis in the urinary bladder.

Clinical Signs

During the treatment period, compared to controls, HDM&Fs had an increased incidence of chromodachryorrhea (red material around the mouth); and males at all doses and HDFs had an increased incidence of chromorhinorrhea (red material around the nose). These observations generally occurred 2 to 4 hours postdose but were reversible during the recovery period. The overall health of the animals was not affected. Given the transient and reversible nature of these findings, they are not considered to be adverse.

Body Weights and Food Consumption

During the treatment period, compared to controls, there were slight decreases in weight gain at all doses in both sexes (~4%) without a clear dose-response relationship or correlative changes in food consumption. The decreases in weight gain were reversible during the recovery period. Because the decreases were of small magnitude and fully reversible, they are not considered to be adverse.

Ophthalmoscopy

Compared to controls, there were no drug-related ophthalmic changes.

Clinical Pathology (Hematology, Coagulation, Clinical Chemistry, and Urinalysis)

There were no drug-related adverse changes in clinical pathology parameters compared to the control group. Mild changes in some parameters were observed in the high dose (HD) group but were reversible (see below), and not considered to be adverse. The low dose (LD) and mid dose (MD) groups were not affected.

Hematology and Coagulation

During the treatment period, compared to controls, HDFs had higher absolute and relative reticulocyte counts (~45%) and a slightly higher hemoglobin distribution width (7.1%). These changes were reversible during recovery. Increased reticulocyte count and hemoglobin distribution width typically suggest a regenerative response to anemic condition. However, there were no correlative findings indicative of bleeding or anemia, and the values were within the historical control ranges at the test facility; therefore, they are not considered to be adverse.

Clinical Chemistry

During the treatment period, compared to controls, HDMs had slightly higher serum levels of albumin (7%) and alkaline phosphatase (32%); HDFs had higher levels of alkaline phosphatase (65%) and cholesterol (60%). These changes correlated with microscopic changes of centrilobular hepatocellular hypertrophy and midzonal vacuolation in the liver. However, the values, despite being higher than concurrent controls, were within the historical control range at 139 Integrated Review Template, version date 2019/10/16

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the test facility and were reversible after recovery. Therefore, the toxicological relevance of these changes appears to be limited.

Urinalysis

Compared to controls, there were no drug-related changes in urinalysis.

Gross Pathology

At the terminal and recovery necropsies, compared to controls, there were no drug-related findings in gross pathology.

Organ Weights

The weight of an adequate number of tissues and organs was measured. At the terminal necropsy, compared to controls, liver weight was slightly increased in HDMs (13.1%) and HDFs (17.1%), which correlated with histopathology findings of hepatocellular hypertrophy and vacuolation and an increased serum alkaline phosphatase level. HDMs also had slightly increased weights (11.5%); however, there were no correlative findings from histopathology, clinical chemistry, or urinalysis. Therefore, the toxicological relevance appears to be limited.

Histopathology

At the terminal and recovery necropsy, an adequate number of tissues/organs from the control and HD groups were evaluated for histopathology. In addition, the liver and pancreas from the animals in the LD and MD groups were evaluated for histopathology. Peer review was conducted. At the terminal necropsy, compared to controls, HDM&Fs had increased incidences of centrilobular hepatocellular hypertrophy and midzonal vacuolation in the liver (Table 93). The vacuolation consisted of small to large clear vacuoles, predominantly in the midzonal region of the lobule but also involving the centrilobular regions. The incidence and severity were slightly higher in HDFs than HDMs, likely due to higher drug exposure in females at the same doses. These changes correlated with increased liver weight and increased albumin, alkaline phosphate, and/or cholesterol levels. These changes were reversible after recovery. One of 11 HDMs (No. 7699) also had mild multifocal liver necrosis and one of 10 LDMs (No 7754) had minimal focal liver necrosis (Table 93). The necrotic foci were well-delineated, randomly distributed, and characterized by liquefactive necrosis and mild infiltration of lymphocytes. Because liver necrosis may occur spontaneously in rats (Greaves 2012), and because it occurred in only a single animal without correlative changes indicative of liver injury (such as inflammation or elevation of liver enzymes), this finding is likely to be incidental. In addition, glandular atrophy in the pancreas was observed in 3/11 control males, 1/10 LDMs, and 3/10 HDFs. Because the incidences were similar between controls and treated animals and because pancreatic atrophy can occur spontaneously in rats (Greaves 2012), it is considered to be incidental.

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Table 93. Histopathology Findings in the Liver at the Terminal Necropsy from the 13-Week Rat Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 22, 87, and 217 mg/kg/day

Toxicokinetics

On days 0 and 85, blood samples were collected from satellite TK animals at 0 (predose), 0.5, 1, 2, 4, 8, and 24 hours postdose8. The TK parameters of viloxazine were determined. On both sampling days, after oral administration, viloxazine was rapidly absorbed and eliminated with a Tmax of 0.5 to 2 hours and a half-life (T1/2) of 0.6 to 3.6 hours. The Cmax increased slightly less than dose proportionally whereas the AUC0-24h increased greater than dose proportionally. Compared to males, females had slightly higher drug exposure; the female-to-male exposure ratio ranged from 1.5 to 1.9. Repeat administrations did not significantly alter drug exposure, and there was no accumulation (Table 94). Table 94. Toxicokinetic Parameters of Viloxazine in the 13-Week Rat Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 22, 87, and 217 mg/kg/day Abbreviations: AUC = area under the curve; NA = not applicable

8 For controls, blood samples were only collected at 1 hour postdose.

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Methods Details Comment on study design This study is a dietary study that includes a 6-month interim and conduct: analysis for all groups10 and a 6-week recovery period for the control and HD groups after 18 months of treatment. A 2-week dosing titration was implemented at the beginning: all viloxazine treatment groups received 17 mg/kg/day in week 1, which increased to 52 mg/kg/day for the MD and HD groups in Week 2, and to 156 mg/kg/day for the HD group in Week 3. During the study (Week 46), due to excessive decreases in weight gain and food consumption, the dose in the HD group was reduced from 156 to 104 mg/kg/day. Dosing solution analysis: The viloxazine-containing diet was prepared weekly. The viloxazine concentration in the diet was confirmed to be within the acceptable range (10% of the proposed dose levels). Source: summarized from the Applicant's study reports

Observations and Results

Mortality

In the interim sub-study, 1/20 HDMs had a broken mandible (jaw bone), which led to inability to eat, subsequent body-weight loss, and early termination. This premature death is not considered to be drug related. Compared to controls, there was no clear trend of drug-related deaths in the study. During the study, 2, 4, 5, and 4 male rats, and 3, 6, 1, and 4 female rats in the control, LD, MD, and HD groups, respectively, (n=42/sex/group) died prematurely (weeks 16 to 78). No causes of death were determined. However, the mortality rate (~6% to 12%, sex combined) is generally within the expected range for spontaneous death in an 18-month rat study. Moreover, the incidence and the time of deaths were comparable across all groups. Therefore, it is unlikely that the deaths are drug related.

Clinical Signs

In the main study, 1 MDM (No. 3136) had convulsions during weeks 73 and 74, which led to early termination in Week 75. Two LDFs (Nos. 2217 and 2216) were ataxic and circling in the cage with head tilt in weeks 68 and 70, respectively, which led to early termination in weeks 69 and 74, respectively. One HDM (No. 4117) was found recumbent in the cage and was euthanized in Week 69. One control female (No. 1236) had several vaginal bleedings throughout the study and was euthanized in Week 78. One control male (No. 1124) was ataxic with head tilt during Week 4 of the recovery phase but survived to the end of the recovery period. Reviewer’s note: The incidence of convulsion and convulsion-related clinical signs (ataxia) was relatively low in this study, and there was no clear dose relationship. However, it should be noted that convulsions and tremors were observed in the 2-year carcinogenicity study after approximately 4 months of dosing at 217 mg/kg/day, and two additional incidences occurred

10 For the 6-month interim analysis substudy, findings for clinical signs, body weight, weight gain, food consumption, clinical pathology were generally similar to those in the main study; therefore, they are not discussed separately. For pathology parameters (gross pathology and histopathology), the results are discussed separately to provide a temporal relationship in terms of the drug-related histopathology changes.

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after the dose was reduced to 130 mg/kg/day. In comparison, in the 13-week study, viloxazine at the same dose of 217 mg/kg/day did not cause any clinical signs indicative of convulsions. It is possible that prolonged repeat drug treatment lowers the convulsion threshold (kindling effect).

Body Weights and Food Consumption

During the treatment period, compared to controls, weight gain and food consumption were decreased in HDM&Fs starting in Week 3 (Figure 28). The decreases in HDMs were generally less than 5%; however, the decreases in HDFs increased with increasing treatment duration from 13% at Week 3 to 17% at Week 46 in food consumption and from 4% at Week 3 to 18% at Week 46 in weight gain. Water intake was also decreased in HDMs (up to ~14%) and HDFs (up to ~27%). Due to the excessive decreases in weight gain and food consumption, the dose was reduced from 156 to 104 mg/kg/day in the HD group. After this dose reduction, no further decreases in food consumption and weight gain were observed. Figure 28. Drug-Related Decreases in Weight Gain and Food Consumption in the 18-Month Rat Study

Source: Excerpted from the Applicant’s study reports

Ophthalmoscopy

Compared to controls, there were no drug-related ophthalmic changes.

Hematology

Blood samples were collected during weeks 14, 27, 38, 53, 77, and 79. An adequate battery of hematology parameters was evaluated. Compared to controls, there were no drug-related adverse changes in hematology parameters. Occasional changes in monocyte counts were observed in individual animals on some but not all sampling days. These are considered to be incidental or non-adverse based on their small magnitude and/or lack of a clear dose relationship.

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Clinical Chemistry

Serum samples were collected at the scheduled interim (month 6, n=10/sex/group) and terminal (month 18, n=14/sex/group) necropsies. An adequate battery of clinical chemistry parameters was evaluated. At the interim necropsy, compared to controls, MDMs and HDMs had slight decreases in glucose (14% to 18%) and triglyceride (42% to 65%) levels. Similarly, at the terminal necropsy, slight decreases in triglyceride levels were observed in MDMs and HDMs (25% to 36%). These decreases are likely secondary to decreased food consumption and weight gain. Given their small magnitude, they are not considered to be adverse. Females were not affected.

Urinalysis

Urine samples were collected during weeks 14, 26, 37, 52, and 77. An adequate battery of urinalysis parameters was evaluated. In addition, urinary ascorbic acid levels were measured in the control and HD groups at the terminal (n=8/sex/group) and recovery (n=5/sex/group) necropsies. Compared to controls, urinary calcium excretion was decreased in the HD group on all sampling days (up to ~55%). The Applicant proposed that the decreases in urinary calcium were secondary to decreased food consumption. This is a reasonable explanation. Because there were no correlative changes in histopathology, the toxicological relevance of these changes appears to be limited. In addition, HDFs had increased urinary ascorbic acid excretion, particularly in Week 26 (~167%); however, at the terminal necropsy, the increase was only ~20%. The biological or toxicological relevance of such changes is likely to be limited11.

Gross Pathology

At the scheduled interim, terminal, and recovery necropsies, animals were evaluated for gross pathology. In addition, their femur length was measured. Compared to the controls, there were no drug-related gross pathology findings at the interim (6 months), terminal (18 months), or recovery necropsies. There were no drug-related changes in femur length.

Organ Weights

The weight of an adequate number of organs was measured. At the 6-month interim necropsy, compared to controls, there were no drug-related changes in organ weights. The HD group had increased relative weights of the liver, brain, and testes, primarily due to a decreased body weight.

11 Extremely high urinary ascorbic acid levels could interfere with the accuracy of some urinalysis parameters; however, at the terminal necropsy, HDFs exhibited an only ~20% increase in urinary ascorbate level; this is unlikely to have a noticeable impact on data collection and interpretation.

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Similarly, at the 18-month terminal necropsy, compared to controls, there were no drug-related changes in organ weights. The MD and HD groups showed dose-dependent increases in the relative weight (relative to body weight) of the liver, heart, kidney, and brain. These increases were mainly due to decreased body weight because the absolute weights of these organs did not change.

Histopathology

At the scheduled necropsy, an adequate number of organs/tissues was evaluated for histopathology. In addition, Oil Red O staining (for lipids) and electron microscopy were conducted to examine hepatic vacuolation. At the 6-month interim necropsy, compared to controls, there were dose-dependent increases in the incidence and severity of hepatocellular vacuolation, which were due to lipid accumulation (Table 96). Table 96. Drug-Related Centrilobular Vacuolation (Lipid Accumulation) at the 6-Month Interim Analysis in the 18-Month Rat Study Centrilobular Fat Control LD MD HD Droplets M F M F M F M F Minimal 9/20 1/20 15/20 4/20 11/20 2/20 1/19 11/20 Moderate 0/20 0/20 5/20 0/20 9/20 2/20 5/19 4/20 Marked 0/20 0/20 0/20 0/20 0/20 0/20 13/19 1/20 Source: Modified/reformatted based on the data in the Applicant’s study reports Abbreviations: HD = high dose; LD = low dose; MD = mid dose At the 18-month terminal necropsy, compared to controls, there were dose-dependent increases in the incidence and severity of hepatocellular vacuolation in MD and HD animals (Table 97). The vacuolated cells were typically enlarged and contained foamy cytoplasm with small, central nuclei or coalesced vacuoles with eccentric nuclei. The vacuolations were primarily due to dose- dependent increases in the amount of fat droplets in hepatocytes (Table 98). At the recovery necropsy, control and HD animals had comparable incidences and/or severities of hepatocellular vacuolation, suggesting recovery. Table 97. Drug-Related Histopathology Changes at the Terminal and Recovery Necropsies in the 18-Month Rat Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 17, 51, and 154/103 mg/kg/day, respectively

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Table 98. Incidence of Hepatocellular Fat Droplets at the Terminal and Recovery Necropsies in the 18-Month Rat Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 17, 52, and 156/104 mg/kg/day, respectively Abbreviations: ORO = Oil Red O

Toxicokinetics

Not conducted.

Other Repeat-Dose Toxicology Studies in the Rat

In a 4-week study (Study 809V-Tox-2007-017, GLP), Sprague-Dawley rats were orally treated with viloxazine at 0 (control), 22 (LD), 87 (MD), and 217(HD) mg/kg/day. Viloxazine at ≥87 mg/kg/day, caused dose-dependent decreases in body weight (up to 7.3%), weight gain (up to 19.2%), and food consumption (up to 14.4%). The decrease in body weight at 217 mg/kg/day persisted after recovery; therefore, it is considered to be adverse. In addition, a micronucleus assay of bone marrow was performed at the end of the treatment period. Compared to controls, viloxazine at doses up to 217 mg/kg/day was not cytotoxic to bone marrow, as demonstrated by the lack of a significant decrease in the polychromatic to normochromatic erythrocyte ratio. Viloxazine treatment at doses up to 217 mg/kg/day did not cause an increase in micronucleated polychromatic erythrocytes. Therefore, viloxazine is negative in the rat bone marrow micronucleus assay. TK parameters were evaluated for both R(+)- and S(-)-viloxazine. In general, the TK profiles for R(+)- and S(-)-viloxazine were similar, and each accounted for approximately 50% of the total exposure of the racemic viloxazine mixture. Females had slightly higher viloxazine exposure than males. For metabolite profiling, a total of 18 metabolites was identified. These metabolites were formed from one or more phase I and phase II metabolic reactions, confirming that viloxazine is extensively metabolized in rat. In general, female rats had more glucuronide conjugates but fewer sulfate conjugates than male rats. Based on the decreased body weight and weight gain, the NOAEL for general toxicity in the 4-week study is 87 mg/kg/day. The corresponding drug exposure levels (AUC) after 4 weeks of repeat treatments were 6834 and 12,523 ng*hour/mL for males and females, respectively.

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In a 7-day study (Study 809V-Tox2007-002, non-GLP) in Sprague-Dawley rats, viloxazine at ≥434 mg/kg/day was not tolerated and caused severe CNS toxicity (convulsions and tremors); excessive decreases in body weight, weight gain, and/or food consumption; and premature deaths. The drug exposures associated with premature deaths were Cmax values of 6623 and 13,600 ng/mL and AUCs of 77,275 and 188,659 ng*hour/mL in males and females, respectively. Doses of up to 217 mg/kg/day were tolerated and the drug effects included hypoactivity, decreased body weight and food consumption. After 7 days of treatment at 217 mg/kg/day, the drug exposures were Cmax values of 4040 and 5495 ng/mL and AUCs of 29159 and 66297 ng*hour/mL in males and females, respectively. 13.2.4.2.2. Repeat-dose Toxicity Studies in Mouse Study title: 4-Week Oral Gavage Toxicity and Toxicokinetic Study with SPN-812V in rasH2 Transgenic Wild- Type mice with 2-Week Recovery Study no.: 812V-Tox2011-00712 Study report location: EDR, SDN-1 Conducting laboratory and location: (b) (4) Duration: 4 Duration units: weeks GLP compliance: Y Drug, lot #, and % purity: Viloxazine; L-8340-101-001; 99.9% Target organ+: CNS Target organ+: LIVER

Key Findings

 There was one potentially drug-related death at 173 mg/kg/day.  Viloxazine caused dose-dependent CNS signs, including hypoactivity and impaired gait at 130 mg/kg/day and convulsions at 173 mg/kg/day.  Viloxazine caused dose-dependent increases in hepatocellular vacuolation (lipid accumulation) and hypertrophy, which correlated with increased liver weight and increased alanine aminotransferase (ALT) level. These changes were reversible after recovery.  Based on the clinical signs and liver findings at ≥130 mg/kg/day, the NOAEL is considered to be 43 mg/kg/day. The corresponding exposure levels after 28 days of repeat treatments are Cmax values of 2618 and 2672 ng/mL in males and females, respectively; and AUCs of 11,593 and 11,809 ng*hour/mL in males and females, respectively.

12 This study also served as the DRF study for the 6-month carcinogenicity study in Tg.rasH2 mice.

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Table 99. A 4-Week Oral Gavage Toxicity and Toxicokinetic Study with Viloxazine in rasH2 Transgenic Wild-Type Mice with 2-Week Recovery Methods Methods Details Doses: 0 (vehicle control), 43 (LD),130 (MD) and 173 (HD) mg/kg/day Frequency of dosing: Once daily Number/sex/group: Main study: n=10/sex/group Recovery: n=5/sex for control and HD groups only TK: n=18/sex for viloxazine treated groups and n=3/sex for controls Dose volume: 10 mL/kg Formulation/vehicle: H2O Route of administration: ORAL GAVAGE Species: MOUSE Strain: CB6F1-TgN (RasH2) Wild Type Age/sexual maturity: Approximately 9-10 weeks at treatment initiation Comment on study design Dose selection was based on a 5-day DRF study (Study 812V- and conduct: Tox2011-006). In this study, viloxazine, caused dose-dependent CNS toxicities, including hypoactivity at doses ≥43 mg/kg/day; impaired gait and a single incidence of convulsion at 130 mg/kg/day; convulsions and lateral recumbency in multiple animals at 217 mg/kg/day; and premature deaths at 433 mg/kg/day. The convulsion and premature death findings at ≥217 mg/kg/day indicate that the MTD was exceeded. Based on the findings, doses of 43, 130, and 173 mg/kg/day were selected. Dosing solution analysis: The concentration of the dosing formulation was confirmed to be within the acceptable range. Source: summarized from the Applicant's study reports

Observations and Results

Mortality

One of 5 HDF died on day 8. The cause of death could not be determined. However, because at the same dose viloxazine caused convulsions in multiple animals, which could lead to premature death, it is possible that this death was drug related.

Clinical Signs

During the treatment period, compared to controls, viloxazine caused dose-dependent CNS effects, including hypoactivity and impaired gait in the MD group and convulsions in the HD group (Table 100). Most of the clinical signs were observed within 1 to 2 hours postdose and were reversible within 4 to 5 hours. All affected animals appeared normal prior to the next dose. The LD group was not affected.

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Table 100. Drug-Related Clinical Signs in the 4-Week Mouse Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 130 and 173 mg/kg/day, respectively

Body Weights and Food Consumption

During the treatment period, compared to controls, there were no significant or adverse changes in body weight or weight gain. MDFs and HDFs had slightly lower body weight and weight gain; however, their magnitude was small (<5%) and they are not considered to be adverse. During the first week of treatment, food consumption was decreased in the MD and HD groups (up to 18%); however, it rapidly recovered and did not lead to adverse decreases in body weight or weight gain. Therefore, the initial decrease in food consumption is not considered to be adverse.

Ophthalmoscopy

There were no drug-related ophthalmic changes.

Hematology

At the terminal necropsy, compared to controls, HDFs had decreased absolute and relative lymphocyte counts (69% and 15%, respectively), which led to a non-significant decrease in the total white blood cell count. There were no correlative histopathology findings indicative of changes in the hematopoietic or lymphoid organs; and the changes were reversible after recovery. Therefore, the toxicological meaning appears to be limited.

Clinical Chemistry

At the terminal necropsy, compared to controls, the alkaline phosphatase level was slightly increased in males at all doses and in MD and HD females (23% to 47%) and the cholesterol level was slightly decreased in MD and HD males and females (28% to 62%). These changes are possibly associated with histopathology findings of hepatocellular vacuolation (lipid accumulation) and hypertrophy in the MD and HD groups. In addition, the glucose level was slightly decreased in MD and HD females (30% to 35%). The hypoglycemic effect is likely 150 Integrated Review Template, version date 2019/10/16

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drug-related but nonadverse, given the small magnitude. These changes were reversible at the end of the recovery period.

Gross Pathology

At the terminal necropsy, pale discoloration (diffuse) in the liver was observed in 1/10 HDMs, 1/10 MDFs, and 5/11 HDFs. In addition, liver enlargement was observed in 1/10 HDMs. These changes are possibly correlative with increased liver weight and the histopathologic findings of hepatocellular vacuolation and hypertrophy.

Organ Weights

At the terminal necropsy, compared to controls, HDFs had slightly increased liver weight (↑11%), which correlated with histopathology of hepatocellular vacuolation and hypertrophy. Spleen weight was slightly decreased in MDFs and HDFs (↓19% in both groups). However, there was no correlative histopathology changes in the spleen; therefore, the toxicological relevance appears limited.

Histopathology

An adequate number of tissues/organs from animals in the control and HD groups was subjected to histopathology examination. In addition, the liver samples and any gross lesions in any group were examined. Peer review was conducted. At the terminal necropsy, compared to controls, there were dose-dependent increases in the incidence and severity of hepatocellular vacuolation and hypertrophy in the MD and HD groups (Table 101). Subsequent Oil Red O staining showed that the vacuolation was due to lipid accumulation (presence of lipid droplets) in the liver. These changes were reversible after recovery. Table 101. Drug-Related Histopathology Changes in the Liver in the 4-Week Mouse Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 43, 130, and 173 mg/kg/day, respectively

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Toxicokinetics

On day 28, blood samples were collected from TK animals at 0.25, 0.5, 1, 4, 8, and 24 hours postdose. A TK analysis of viloxazine was conducted.

After oral administration, viloxazine was rapidly absorbed and eliminated, with a Tmax generally of 0.25 to 1 hour (except for MDM) and a T1/2 of ~2 hours. The exposure (AUC) increased in proportion to the dose. There was no significant different in exposure between males and females (Table 102). Table 102. Toxicokinetic Parameters of Viloxazine in the 4-Week Mouse Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 43, 130, and 173 mg/kg/day, respectively Abbreviations: AUC = area under the curve 13.2.4.2.3. Repeat-dose Toxicity Studies in the Dog Study title: A 13-Week Oral (Capsule) Toxicity and Toxicokinetics Study of SPN-809V in Beagle Dogs with a 4-Week Recovery Period Study no.: 809V-Tox2009-005 Study report location: EDR, SDN-1 Conducting laboratory and location: (b) (4) Duration: 13 Duration units: weeks GLP compliance: YYY Drug, lot #, and % purity: Viloxazine; CMLW-147/08-VL3; 100% Target organ+: CNS

Key Findings

 Viloxazine at 39 mg/kg/day caused continuous convulsions, intermittent tremors, altered respiration, and/or impaired muscle coordination, which led to early termination of the animals.  Viloxazine at all doses decreased body weight, weight gain, and food consumption; the decreases were most profound and considered to be adverse at doses ≥22 mg/kg/day. These effects were reversible after recovery.  Based on the findings, the NOAEL is considered to be 8.7 mg/kg/day in this study. The corresponding exposure levels after 85 days of repeat treatments are Cmax values of 2660 and 2730 ng/mL in males and females, respectively; and AUCs of 13,200 and 14,700 ng*hour/mL in males and females, respectively.

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Table 103. A 13-Week Oral (Capsule) Toxicity and Toxicokinetics Study of SPN-809V in Beagle Dogs with a 4-Week Recovery Period Methods Methods Details Doses: 0 (control), 8.7 (LD), 22 (MD), and 39 (HD) mg/kg/day Frequency of dosing: Once daily Number/sex/group: Main study: n=4/sex/group Recovery: n=2/sex for the control and HD groups only Dose volume: NA; viloxazine powder was administered in gelatin capsules (not liquid form) Formulation/vehicle: Gelatin capsules Route of administration: ORAL Species: DOG Strain: BEAGLE Age/sexual maturity: 5-6 months of age at treatment initiation Comment on study design Dose selection was based on previous 7-day and 4-week studies and conduct: (Studies 809V-Tox2007-003 and 809V-Tox2007-018, respectively). In the 7-day study, viloxazine at 87 mg/kg/day exceeded the MTD and caused convulsions, body weight loss, ataxia, and lateral recumbency, which led to early termination. In the 4-week study, no toxicity was observed at 4 mg/kg/day. At 22 mg/kg/day, viloxazine caused mild and reversible toxicities of decreased body weight, weight gain and food consumption. At 52 mg/kg/day, viloxazine also caused poor clinical condition and premature deaths. Based on these findings, 39, 22, and 8 mg/kg/day were selected as the high, middle, and low doses in the current study. Dosing solution analysis: The stability of viloxazine powder was confirmed to be acceptable for use in this study. Source: summarized from the Applicant's study reports

Observations and Results

Mortality

There were 4 premature deaths in the study, all in the HD group (3/6 HDMs and 1/6 HDF), 3 of which were likely drug-related. Two HDMs (Nos. 6830 and 6833) were euthanized on day 83 and 86, respectively, due to drug-related severe toxicities (prolonged convulsions, intermittent tremors, altered respiration, and/or impaired muscle coordination). Animal 6830 had repeated convulsions that led to dose cessation; however, the convulsions continued and eventually led to early termination of the animal. A post mortem examination revealed degeneration of the heart and skeletal muscle and elevated aspartate aminotransferase (AST) and sorbitol dehydrogenase levels, likely secondary to prolonged muscle exertion during convulsions. Animal 6833 was euthanized on day 86 due to severe convulsions and poor clinical condition (inactivity, prostration, and rigid muscle tone). A post mortem examination did not identify any abnormal clinical pathology, necropsy, or histopathology findings in this animal. Nevertheless, given the similarity of findings in HD animals, it is considered to be drug related. One additional HDM (no. 6836) was euthanized on day 18 due to poor physical condition, including impaired balance, inactivity, hunched posture, hyper-reactivity to touch, and fever (103.5°F). Clinical observations in this animal included intermittent tremors and hypoactivity on day 1, slight weight loss and decreased food consumption in Week 1, and repeated excessive salivation and emesis prior to day 18. A post mortem examination revealed bacterial plaque at 153 Integrated Review Template, version date 2019/10/16

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the aorta and an increased neutrophil count, suggesting infection as a potential cause of death. However, given the CNS effects and the high incidence of mortality in the HD group, the contribution of viloxazine to the general poor condition of the dog cannot be excluded. One HDF (no. 6864) was euthanized on day 1 due to poor condition, including inactivity and abnormal respiration. A post mortem examination revealed necrosis, hemorrhage, and acute inflammatory infiltrates in the alveolar tissue, with extension through the pleura and involving the pericardium. Based on these findings, the death was likely due to aspiration of fluid (vomitus), rather than a direct drug effect. Because the mortality occurred on day 1, this animal was replaced with another female.

Clinical Signs

During the treatment period, compared to controls, multiple adverse effects, including tremors, convulsions, hypoactivity, rigid muscle tone, hyperactivity to touch, twitching, and/or hunched posture, were observed in HDMs, including the 3 HDMs that died prematurely. In 1 HDM (No. 6849), twitching, intermittent convulsions, tremors, rigid muscle tone, and white frothy material around the mouth (emesis) were observed from days 77 to 82. This animal survived and the clinical signs were not noted during the recovery period; also, there were no histopathology findings in the CNS or muscle in this animal at the recovery necropsy. Other drug-related clinical signs in surviving animals included an increased incidence of reddened ears in MDM&Fs and HDM&Fs; mucoid feces in MDMs; and emesis containing white, yellow, and/or capsule material in HDM&Fs. LD animals were generally unaffected. Reviewer’s note: Emesis in HD animals, particularly with capsule materials, may lead to inaccurate/reduced drug doses.

Body Weights and Food Consumption

During the treatment period, compared to controls, body weight and weight gain decreased dose dependently (Figure 29). At the terminal necropsy, compared to controls, the mean body weight was decreased by 3.1%, 19.7%, and 22.8% in LD, MD, and HD males, respectively; and by 7.3%, 13.5% and 12.5% in LD, MD, and HD females, respectively. At the end of the treatment period, cumulative weight gain was decreased by 0.1, 2.5, and 2.9 kg in LD, MD, and HD males, respectively; and by 0.7, 1.2, and 1.3 kg in LD, MD, and HD females, respectively. The decreases in body weight and weight gain correlated with decreased food consumption during the first 3 weeks of treatment. From Week 3 until the end of the treatment period, dietary supplementation was provided to all MD and HD animals, which alleviated the decreases in food consumption. In the LD group, which did not receive dietary supplementation, food consumption remained slightly lower than in the controls throughout the treatment period. During the recovery period, dietary supplementation continued to be provided to HD animals. The body weight, weight gain, and food consumption of the HD animals were generally comparable to controls, suggesting recovery.

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Figure 29. Drug-Related Decreases in Body Weight and Weight Gain during the Treatment Period in the 13-Week Dog Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 8.7 (LD), 22 (MD), and 39 (HD) mg/kg/day, respectively Abbreviations: HD = high dose; LD = low dose; MD = mid dose

Ophthalmoscopy

There were no drug-related ophthalmic findings.

ECG

Compared to controls, there were no drug-related adverse changes in ECG parameters. One of 4 MDMs (No. 6838) had infrequent arterial premature contraction in Week 12. Given the single incidence and lack of similar findings at higher doses, it is considered to be a normal variant. One of 2 HDFs (no. 6857) had infrequent second-degree atrioventricular block in the final week of recovery (Week 17), which is also considered an incidental finding because the animal has not been dosed for 4 weeks. Compared to controls, HDFs had decreased heart rate in Week 12 (95 bpm compared to 134 bpm in controls, a decrease of 39 bpm*); however, the values were within the normal range; therefore, they are not considered to be adverse. *Reviewer’s note: A similar finding of a decreased heart rate relative to concurrent controls was also observed in the 4-week dog study at similar doses. These decreases may be related to desensitization of the adrenergic effects after repeated exposure to viloxazine. In both studies, the magnitude was small, and the values were within the normal range; therefore, they are not considered to be adverse. At the end of the treatment period, compared to controls, the QTc interval was slightly longer in MDFs and slightly shorter in HDMs (Table 104). Because the magnitude of changes was small and their direction was inconsistent and lacked a clear dose relationship, these small changes in QTc are considered to be within normal variations and non-adverse. Table 104. QTc Interval at the End of the Treatment Period in the 13-Week Dog Study Dose/QTc (ms) 0 mg/kg/day 8 mg/kg/day 22 mg/kg/day 39 mg/kg/day Males 236±4.8 233±8.7 225±6.2 223±5.6* Females 184±4.2 182±7.0 180±8.4 198±11.2* Source: Modified/reformatted based on the data in the Applicant’s study reports * p<0.05 compared to concurrent controls 155 Integrated Review Template, version date 2019/10/16

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Hematology and Coagulation

At the terminal necropsy, compared to controls, HDMs had increased basophil and large unstained cell counts (by 100% and 125%, respectively); these values were also higher than the pretreatment baseline (by 30% and 50%, respectively). The basophil counts exceeded the historical control range at the test facility. Therefore, they are considered to be drug related. However, there were no correlative histopathology findings, and the changes were reversible after recovery; therefore, they are not considered to be adverse.

Clinical Chemistry

At the terminal necropsy, compared to controls, triglyceride levels were decreased in MD and HD groups (by 42.9%, 35.7%, 43.5%, and 21.7% in MDMs, HDMs, MDFs, and HDFs, respectively). These values were also lower than the pretreatment baseline values, and likely secondary to decreased body weight, weight gain, and/or food consumption. Also, the changes were reversible after recovery. HDFs also had decreased creatinine (33%) relative to controls; however, this was mainly due to an increase in controls relative to pretreatment baseline values rather than a drug effect in the treatment group.

Urinalysis

There were no drug-related changes in urinalysis parameters.

Gross Pathology

At the scheduled terminal and recovery necropsies, there were no drug-related gross pathology findings.

Organ Weights

At the terminal necropsy, compared to controls, the absolute and relative (to body or brain) liver weights were increased in females at all doses without a clear dose-relationship (up to 14% and 34% in absolute and relative liver weights, respectively). Liver weight was also increased in the only surviving HDM (26% and 16% in absolute and relative liver weights, respectively). There were no correlative histopathology findings in the liver or changes in clinical chemistry indicative of liver damage; in addition, these changes were reversible after recovery; therefore, they are not considered to be adverse. Other changes in organ weights included decreased absolute heart weight in MDMs, decreased absolute kidney weight in MDFs, and increased relative thymus weight in MDFs. These were primarily secondary to decreased body weight rather than a direct drug effect on the organs/tissues.

Histopathology

An adequate number of tissues/organs of the animals in the control and HD groups (including the 2/4 pre-mature death HDMs that were treated for 83 and 86 days, respectively*) was subjected to 156 Integrated Review Template, version date 2019/10/16

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histopathology evaluation. In addition, gross lesions in animals in all groups were evaluated for histopathology. Peer review was conducted. At the terminal and recovery necropsies, compared to controls, there were no drug-related abnormal histopathology findings. *Reviewer’s note: Due to premature deaths, only 1/4 HDM was evaluated for histopathology at the scheduled terminal necropsy. The MD and LD groups were not subjected to a full histopathology evaluation (only gross lesions were evaluated), which could have resulted in an inadequate histopathology evaluation. However, 2/4 HDMs were euthanized and evaluated for detailed histopathology on days 83 and 86, respectively, near the end of the treatment period. Therefore, a total of 3 HDMs was treated for an adequately long period (≥83 days), and the histopathology evaluation in this study is considered to be acceptable.

Toxicokinetics

Blood samples were collected on days 0 and 85 at 0 (predose), 1, 2, 4, 8, 12, and 24 hours postdose. A TK analysis of viloxazine was conducted. On both sampling days, after oral administration, viloxazine was relatively rapidly absorbed, with a Tmax of 1 to 2.5 hours on day 0 and 2.5 to 2.5 hours on day 85. The mean half-life T1/2 was 1.9 to 2.5 hours on day 0 and 1.7 to 2.7 hours on day 85. There was no sex difference in viloxazine exposure. On both sampling days, the exposure levels (Cmax and AUC) increased dose proportionally. Repeat administrations did not lead to drug accumulation (Table 105). Table 105. Toxicokinetic Parameters of Viloxazine in the 13-Week Dog Study Doses Tmax (h) T1/2 (h) Cmax (ng/mL) AUC (ng*hour/mL) (mg/kg/day) M F M F M F M F Day 0 8 (LD) 1.3 2.5 2.2 2.0 3530 2370 12100 10000 22 (MD) 2.3 1.8 1.9 2.5 9070 7530 44600 37600 39 (HD) 2.0 1.0 2.5 2.5 16900 14700 94100 63300 Day 85 8 (LD) 2.8 2.5 2.1 1.7 2660 2730 13200 14700 22 (MD) 5.5 4 1.5 1.8 5720 6660 47600 36800 39 (HD) 3.3 3.2 2.7 1.8 9470 8960 64200 55500 Source: Modified/reformatted based on the data in the Applicant’s study reports Abbreviations: AUC = area under the curve; HD = high dose; LD = low dose; MD = mid dose; T = time *Reviewer’s note: TK samples were collected from the HDM (No. 6849) that had convulsions. However, the drug exposure levels in this animal were comparable to the group mean values, suggesting that the convulsions were not due to abnormally high drug exposure.

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Study title: Viloxazine Hydrochloride: A 12-Month Oral Toxicity Study in Dogs Study no.: 725-0016 Study report location: EDR, SDN-2 Conducting laboratory and location: (b) (4) Duration: 12 Duration units: months GLP compliance: N Drug, lot #, and % purity: Viloxazine; PDRM W0058 and 0091; 99.3% and 99.2%13 Target organ+: LIVER Reviewer’s note: This is a legacy study primarily focused on histopathology evaluation of viloxazine treated animals at 6 months (interim), 12 months (terminal), and after 4 and 8 weeks of recovery.

Key Findings

 Viloxazine caused hepatocellular enlargement, intracytoplasmic inclusions, and lipid droplet accumulation in the liver. These changes occurred prior to 6 months of repeat treatments and were reversible after 4 to 8 weeks of recovery. Table 106. Viloxazine Hydrochloride: A 12-Month Oral Toxicity Study in Dogs Methods Methods Details Doses: 0 (control), 3.5 (LD), 10 (MD), and 10/21/31/36/42 mg/kg/day Dose titration was conducted for the HD group: started at 10 mg/kg/day for 1 week and escalated to 21, 31, 36, and 42 mg/kg/day at weeks 2, 3, 17, and 19, respectively. Frequency of dosing: Once daily Number/sex/group: Main study (12-month treatment): n=4/sex for control; n=6/sex for LD; n=5/sex for MD; and n=4/sex for HD Interim analysis (6-month treatment): n=5/sex/group 4-Week recovery: n=1/sex for control; n=1/sex for MD; n=2/sex for HD 8-Week recovery special evaluation for liver: n=2/sex for control; n=3/sex for HD Dose volume: NA, animals were dosed in gelatin capsules Formulation/vehicle: Gelatin capsules Route of administration: ORAL Species: DOG Strain: BEAGLE Age/sexual maturity: 6–7 months at treatment initiation Comment on study This study has a complicated design, with multiple groups primarily design and conduct: designated for evaluation of liver-related histopathology findings at different time points (see above). Clinical signs and body weights were not included as regular endpoints. Dosing solution analysis: Not included in the study report Source: summarized from the Applicant's study reports

13 This report did not include purity information on the viloxazine lots used in the study. However, the same lots were also used in the 18-month rat study; therefore, the purity information from the 18-month rat study was listed.

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Observations and Results

Mortality

One HDF (no. 76-987) died in Week 52. In the study report, it was stated that due to “CNS signs”, this animal received multiple dosing holidays and/or dose adjustment, including “7/21 no dose; 7/29-8/5 no dose; 8/6-8/13 36 mg/kg; 8/14-8/16 no dose; 8/17-9/7 24 mg/kg; 9/8-9/12 36mg/kg; 9/13-9/16 48 mg/kg; 9/16 dead.” Although no detailed description of the clinical signs or moribund conditions was provided, given the information on the CNS effects of viloxazine, it is reasonable to conclude that this premature death is drug related. One HDM (no. 76-441) died in Week 34. There were no remarkable moribund findings in this animal. Post mortem necropsy findings did not indicate a clear relationship with viloxazine. However, given that a potentially drug-related death occurred at the same dose (No. 76-987), a role for viloxazine in this animal’s death cannot be excluded. One HDM (no. 76-360) was euthanized in Week 32 due to necrotizing gingivitis. Because there are no similar findings in any of the nonclinical studies and because there is no plausible mechanism for viloxazine to cause gingivitis, this death is considered to be incidental.

Gross Pathology

At the 6-month interim necropsy, compared to controls, there were dose-dependent increases in the incidence of liver color changes, from a dark tan to a pale tan. The incidence increased from 0/6 in the control group to 2/10, 6/10, and 7/10 in the LD, MD, and HD groups, respectively. Similar to the interim analysis, at the terminal necropsy, compared to controls, the MD and HD groups exhibited dose-dependent increases in the incidence of liver color change, tan, mottling with distinct acinar patterns, or purple mottling (Table 107). These correlated with histopathology findings of hepatocellular enlargement (hypertrophy), intracytoplasmic inclusions, and lipid accumulation in the liver. Table 107. Drug-Related Gross Pathology Changes in the Liver at the Terminal Necropsy in the 12-Month Dog Study

Source: Excerpted from the Applicant’s study reports Abbreviations: HD = high dose; LD = low dose; MD = mid dose

Clinical Pathology

At the 6-month interim necropsy, compared to controls, HDMs had higher white blood cell counts (~50%), with no correlative findings in histopathology or in bone marrow assessment. Therefore, these changes are not considered to be adverse.

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No other drug-related changes in clinical pathology parameters were observed.

Histopathology

At the scheduled necropsy (6-month interim, 12-month terminal, and 4-week recovery), control and HD animals were subjected to a full histopathology evaluation. LD and MD animals were evaluated for histopathology findings in the liver, lung, testis, and any gross lesions. For the 8-week recovery group, liver samples were evaluated for histopathology. In addition, liver samples from the right central hepatic lobe of all animals were processed and evaluated by electron microscopy. At the terminal necropsy, compared to controls, there were dose-dependent histopathology findings in the liver—including hepatocellular hypertrophy, intracytoplasmic inclusions, and lipid droplet accumulation—at all doses (Table 108). When evaluated by electron microscopy, the inclusion bodies appeared to be heterogeneous dense bodies and myelin figures (myeloid bodies). The heterogeneous dense bodies are composed of whirls of endoplasmic reticulum without a limiting membrane, arranged in a lamellar pattern around mitochondria, lipid, or amorphous material, which subsequently became “myelin figures/myeloid bodies,” a form of secondary lysosomes. Cytoplasmic glycogen in hepatocytes was not affected by viloxazine treatment. The Applicant proposed that such changes were most likely associated with hypertrophic endoplasmic reticulum (Ghadially 1982), which appears to be reasonable. It should be noted that similar histopathology findings in the liver were also observed at the 6-month interim necropsy, including dose-dependent increases in intracytoplasmic inclusions and lipid droplet accumulation, which suggest that the gross pathology and histopathology changes in the liver occurred prior to 6 months of viloxazine treatment. These histopathology changes in the liver were generally reversible. After 4 weeks of recovery, compared to controls, the histopathology findings in the liver were limited to minimal numbers of cytoplasmic inclusion bodies/myelin figures in HD animals, as opposed to moderate to marked numbers at the terminal necropsy. There were no findings of hepatocellular hypertrophy, heterogeneous dense bodies, or lipid droplet accumulation after 4 weeks of recovery. After 8 weeks of recovery, there were no liver histopathology findings in the 4 HD animals (1 M/3 Fs) evaluated, suggesting full recovery.

Special Evaluation

At both the 6-month interim necropsy and the 12-month terminal necropsy, bone marrow smear samples were collected and evaluated for bone marrow cellularity. There were no drug-related changes in the bone marrow.

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Table 108. Drug-Related Histopathology Changes in the Liver at the Terminal Necropsy in the 12-Month Dog Study

Source: Excerpted from the Applicant’s study reports Type I, dense cytoplasmic tiny and small droplets; type II, moderate cytoplasmic tiny and small droplets; type III, moderate cytoplasmic tiny, small, and medium droplets; type IV, sparse cytoplasmic tiny droplets; type V, sparse cytoplasmic tiny and small droplets; type VI, sparse cytoplasmic small and medium droplets; type VII, dense cytoplasmic tiny, small, and medium droplets Abbreviations: HD = high dose; LD = low dose; MD = mid dose

Other Repeat-Dose Toxicology Studies in Dog

Four-week Repeat-Dose Study in Dog (Study 809V-Tox2007-018, GLP)

In a 4-week study, beagle dogs were orally treated with viloxazine at doses of 0 (control), 4 (LD), 22 (MD), and 52 (HD) mg/kg/day. Viloxazine at 52 mg/kg/day resulted in a poor clinical condition and premature deaths. Other findings at this dose included lymphocyte depletion in the 161 Integrated Review Template, version date 2019/10/16

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thymus with correlative decreased thymus weight in both sexes and arterial inflammation or degeneration in males. These findings were most likely secondary to the stress and poor condition of the animals, rather than a direct drug effect, and were reversible after recovery. At ≥22 mg/kg/day, compared to controls, viloxazine caused dose-dependent decreases in body weight (7% to 13%), weight gain (0.5 to 1.1 kg), and food consumption (22 to 41%). The decreases were reversible after recovery. No drug-related neurological effects were observed at any dose. A chiral-specific TK analysis and qualitative metabolic profiling revealed that after oral administration, viloxazine was extensively metabolized in dog; 22 metabolites were identified. The exposure level to R(+)-viloxazine was slightly higher than that to S(-)-viloxazine in dog, with an R-to-S ratio of approximately 7:3 (slightly different from the rat, in which R-and S- viloxazine had comparable exposure levels). Based on the premature deaths and decreased body weights, the NOAEL in this study is 4 mg/kg/day. The corresponding exposure levels after 27 days of repeat treatments are Cmax values of 1002 and 983 ng/mL in males and females, respectively; and AUCs of 3089 and 3446 ng*hour/mL in males and females, respectively.

Sixteen-Week Repeat-Dose Study in Dog (Study (b) (4) -205, non-GLP)

In a 16-week study of potential drug-related pathological changes, beagle dogs were orally dosed with placebo gelatin capsules as the control group (n=1/sex), or viloxazine (n=6/sex) at the maximal tolerated dose (MTD, ~60 to 70 mg/kg/day, defined by anorexia and clinical signs). Animals were initially dosed at 20 mg/kg/day, and gradually titrated down to the MTD at 10 mg/kg/day. One of 6 males and 2/6 females died prematurely after 8, 41, and 102 days of treatment, respectively. Each death was preceded by convulsions. The deaths were mainly due to respiratory asphyxiation and cardiac arrest that occurred during prolonged periods of severe muscle contractions and convulsions. The post mortem histopathology findings included vascular congestion and neuronal vacuolation in numerous neurons of the cerebral cortex and deep nuclei. The vacuoles were tiny, clear, multiple, and occupied the peripheral cytoplasm and their contents were not stainable with several common staining methods. It is unclear whether these neuronal findings were directly due to drug-induced neurotoxicity or secondary to prolonged convulsion and asphyxiation or post mortem autolysis/degeneration. In dogs that survived to the scheduled necropsy, drug-related toxicities included moderate-to- severe anorexia, decreased body weight and weight gain, decreased motor activity, straightened and stiff hindlegs, ataxia, and convulsions. These clinical signs generally occurred within 1 hour postdose and lasted for about 1 to 1.5 hours; no correlative histopathology findings were observed in the brain. At the scheduled necropsy, compared to controls, 2 male and 2 female dogs in the treated group had small hepatocellular eosinophilic bodies (hyaline bodies) and variable-sized lipid vacuoles in the liver. The nuclei were not affected. The hyaline bodies morphologically resembled some cytoplasmic inclusion bodies that were shown to be proliferated smooth endoplasmic reticulum, lipid droplets, and myelin figures in the previous 12-month dog study (Study 725-0016), which were reversible.

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Together, these data showed that viloxazine at 60 to 70 mg/kg/day caused severe convulsions that led to premature death in some dogs and histopathology findings of neuronal vacuolation. In animals that survived to the scheduled necropsy, viloxazine caused inclusion bodies in the liver that were likely reversible. No other histopathology findings were observed in other organs/tissues, including the brain, spinal cord, and kidney. 13.2.5. Genetic Toxicology 13.2.5.1. In Vitro Reverse Mutation Assay in Bacterial Cells (Ames) Study title: Salmonella-Escherichia coli/Mammalian- Microsome Reverse Mutation Assay with a Confirmatory Assay Study no.: 809V-Tox2007-024 Study report location: EDR Conducting laboratory and location: (b) (4) Date of study initiation: 07/06/2007 GLP compliance: Yes QA statement: Yes Drug, lot #, and % purity: Viloxazine (SPN-809V); 1009-30-2; 98.61%

Key Study Findings

Viloxazine was negative in an adequate Ames assay. Table 109. Salmonella-Escherichia coli/Mammalian-Microsome Reverse Mutation Assay with a Confirmatory Assay Methods Methods Details Strains: TA98, TA100, TA1535, TA1537, WP2uvrA Concentrations in 0 (vehicle control), 29, 87, 289, 867, 2166, and 4333 µg/plate in the definitive study: presence and absence of S9 metabolic activation Basis of concentration Dose selection was based on a DRF study in TA100 and WP2uvrA, in selection: which no cytotoxicity was observed at doses up to 5000 µg/plate viloxazine hydrochloride in the presence of S9. In the absence of S9, cytotoxicity was observed at ≥3330 µg in TA 100. No precipitation was observed at up to 5000 µg/plate. Therefore, 5000 µg/plate viloxazine hydrochloride, which is equivalent to 4333 µg/plate viloxazine free base, was selected as the high dose for the definitive study. Negative control: Reverse-osmosis water Positive control:

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Methods Details Formulation/vehicle: Reverse osmosis water Incubation & sampling Plate incorporation method was used. One-hundred microliters of tester time: strain and 200 µL of viloxazine or positive/negative controls were mixed with molten selective top agar in the presence or absence of S9 metabolic activation mix and then overlaid on the minimal bottom agar. Plates were inverted and incubated for 52±4 hours at 37±2°C before they were scored. Each concentration was tested in triplicate. Source: summarized from the Applicant's study reports

Study Validity

Based on the following evidence, I consider the study to be valid:  Three independent GLP-compliant assays were conducted.  An adequate number of plates was evaluated.  Tester strain selection and top dose selection were adequate.  Positive and negative control values were within the expected range of historical controls.  S10 metabolic activation (10%) is adequate.

Results

In the initial assay (Trial 29073-B1), the values of the negative vehicle control in TA100 in the presence and absence of S9 were out of the historical control range (~370 revertants compared to ~110 revertants in the historical control range). Therefore, a second assay (Trial 29073-D1) was conducted in TA 100 only, which generated acceptable values. In addition, due to the unexpected values in the initial assay, a confirmatory assay (Trial 29073-C1) was performed. Based on the overall data from the three assays, both the negative and positive control values were within the historical range. Compared to vehicle controls, viloxazine at concentrations up to 4333 µg/plate (5000 µg/plate viloxazine hydrochloride) was not mutagenic in any of the test strains in the presence or absence of metabolic activation. 13.2.5.2. In Vitro Assays in Mammalian Cells Study title: Chromosomal Aberrations in Cultured Human Peripheral Blood Lymphocytes Study no.: 809V-Tox2007-025 Study report location: EDR Conducting laboratory and location: (b) (4) Date of study initiation: 07/03/2007 GLP compliance: Yes QA statement: Yes Drug, lot #, and % purity: Viloxazine (SPN-809V); 1009-30-2; 98.61%

Key Study Findings

Viloxazine was not clastogenic in an adequate in vitro chromosomal aberration assay in cultured human lymphocytes. 164 Integrated Review Template, version date 2019/10/16

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Table 110. Chromosomal Aberrations in Cultured Human Peripheral Blood Lymphocytes Methods Methods Details Cell line: Human peripheral blood lymphocytes Concentrations in definitive study: Experiment 1: +S9: 0 (vehicle control), 18, 25, 36, 51, 73, 105, 150, 2114, 306, 437, 624, 893, 1274, 1820, and 2560 µg/mL. Experiment 2: -S9 3-hour incubation: 217, 433, 867, 997, 1127, 1213, 1300, 1386, 1473, 1603, 1733, and 2166 µg/mL (1127, 1300, 1386, and 1473 µg/mL were scored because 1473 µg/mL caused a ~52% reduction in mitotic index) Basis of concentration selection: The high dose of 2560 µg/mL was selected to achieve >10mM14. At the high dose there was no precipitation or any significant change in osmolality. Negative control: Reverse osmosis water Positive control: -S9: mitomycin (MMC) +S9: cyclophosphamide (CP) Formulation/vehicle: Reverse Osmosis water Incubation and sampling time: +S9: ~3 hours -S9: ~3 hours and ~22 hours Source: summarized from the Applicant's study reports

Study Validity

The study is valid. The negative and positive controls generated the expected responses. The high dose selection was adequate. The S9 concentration (1.5%) was within the acceptable range (1 to 10%)15.

Results

In the presence of metabolic activation and after 3 hours of incubation, viloxazine at doses of 624, 893, 1274, and 1820 µg/mL did not induce chromosomal aberrations. Doses higher than 1820 µg/mL were cytotoxic. In the absence of metabolic activation and after 3 hours of incubation, viloxazine at doses of 1127, 1300, 1386, and 1473 µg/mL did not induce chromosomal aberrations. Doses higher than 1473 µg/mL were cytotoxic. When incubated for 22 hours, viloxazine at concentrations of 150, 214, 306, and 437 µg/mL did not induce chromosomal aberrations. Concentrations higher than 437 µg/mL were cytotoxic.

14 Current ICHS2(R1) recommends selection of a high dose at 1mM. However, the original ICHS2 1997 recommended selection of a high dose at 10mM; therefore, it is acceptable to use 10 mM as the high dose instead of 1mM.

15 Although 1.5% S9 is at the lower end of the acceptable range, the study report stated that this concentration has consistently caused the positive control (CP) to be highly clastogenic for multiple lots at the test facility.

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13.2.5.3. In Vivo Clastogenicity Assay in Rodent (Bone Marrow Micronucleus Assay) The in vivo micronucleus assay was incorporated into a 4-week repeat-dose general toxicology study in rat. Viloxazine at doses up to 217 mg/kg/day was negative in the rat bone marrow micronucleus assay (Study Supernus 809V-TOX2007-017, see Section III.13.2.4). 13.2.6. Carcinogenicity Study 13.2.6.1. Two-year Oral Gavage Carcinogenicity Study of Viloxazine in Wistar Rats Study no.: 812V-Tox2014-002 Study report location: EDR, SDN-1 Study initiation date: March 7, 2014 Conducting laboratory and location: (b) (4) GLP compliance: Yes Drug, lot #, and % purity: Viloxazine; 5002946/130032; 100.5% Prior exec CAC dose concurrence: Y Basis for dose selection: Dose selection was based on a 13-week study in Sprague-Dawley rats, in which severe CNS toxicity such as convulsions was observed at oral doses ≥433 mg/kg/day, whereas doses up to 217 mg/kg/day were tolerated. ECAC initially recommended doses of 30, 87, and 217 mg/kg/day for LD, MD, and HD, respectively, based on MTD. During the study, due to severe CNS toxicity and mortality, doses were reduced twice to the final doses of 22, 43, and 87 mg/kg/day for LD, MD, and HD, respectively.

Key Findings

 Viloxazine did not increase the incidence of tumors in rats treated for 2 years at oral doses of 30/22, 87/65/43, and 217/130/87 mg/kg/day. The final high dose of 87 mg/kg/day is approximately equal to the MRHD of 400 mg, based on mg/m2 in children16.  Viloxazine at ≥130 mg/kg/day caused CNS toxicities (convulsions and tremors) and premature deaths in both sexes, which led to dose reductions. No further drug-related CNS toxicities were observed after doses were reduced to ≤87 mg/kg/day. Mortality was significantly increased in HD males. Reviewer’s note: Although a TK analysis was conducted in this study, the last TK samples were collected on day 180, prior to the final dose reduction on day 197. The exposure level on day 180 is not an accurate representation of the drug exposure for the majority of the treatment duration. Therefore, the exposure multiple is calculated based on mg/m2 rather than AUC.

16 Because the proposed indication is for the pediatric population only (patients with ADHD ages 6 to 17 years), 2 mg/m -based safety margins are calculated using the average child body weight of 20 kg and conversion factor Km of 25.

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Table 111. Methods for Study 812V-Tox2014-002 Methods Details Doses: 0 (control), 30/22 (LD), 87/65/43 (MD), 217/130/87 (HD) mg/kg/day 17 Frequency of dosing: Once daily Number/sex/group: Main study: n=65/sex/group TK: n=12/sex/group Dose volume: 10 mL/kg Formulation/vehicle: H2O Route of administration: ORAL GAVAGE Species: RAT Strain: WISTAR Age: Five to seven weeks at treatment initiation Comment on study design See comments on dose selection and rat strain differences. and conduct: Dosing comments (dose Due to CNS toxicity (tremors and convulsions) and mortality in HD, adjustments or early doses were first reduced from 217 and 87 mg/kg/day to 130 and 65 termination): mg/kg/day on day 130 in HD and MD, respectively. After the first dose reduction, some HD animals continued to show convulsions from day 187 and mortality from day 191. Consequently, doses were further reduced from 130, 65, and 30 mg/kg/day to 87, 43, and 22 mg/kg/day in HD, MD, and LD, respectively, on day 197. These dose reductions were implemented with ECAC agreement/recommendation. Dosing solution analysis: The concentration of the dosing formulation was within the acceptable range. Source: summarized from the Applicant's study reports

Observations and Results

Mortality

Five drug-related premature deaths occurred at the HD. Specifically, 2/65 HDMs (No. 4191 and 4228) and 1/65 HDF (No. 4452) died during days 123 to 126, which led to dose reductions from 217 and 87 mg/kg/day to 130 and 65 mg/kg/day in HD and MD, respectively, on day 130. After the initial dose reduction, two further HDFs died on days 191 and 193, which led to dose reductions from 130, 65, and 30 mg/kg/day to 87, 43, and 22 mg/kg/day in HD, MD, and LD, respectively, on day 197. No definitive cause of death was identified by the Applicant; however, prior to death, these animals had convulsions, which could have contributed to the deaths. At the scheduled necropsy, there were 54 (83%), 50 (77%), 48 (74%), and 42 (65%) male rats and 51 (78%), 47 (72%), 50 (77%), and 44 (68%) female rats in the control, LD, MD, and HD groups, respectively (Figure 30). Based on Dr. Mbodj’s statistical analysis, compared to controls, there is a statistically significant dose response in the mortality of male rats (p=0.0106) and the mortality rate was significantly increased in HDMs (p=0.011). The mortality rate in females was not affected by viloxazine.

17 Doses are presented as free base-equivalent doses. The original doses of 0, 35/25, 100/75/50, and 250/150/100 mg/kg/day viloxazine hydrochloride are converted to free base-equivalent doses using a correction factor of 0.867.

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Figure 30. Kaplan–Meier Survival Curves in the 2-Year Rat Carcinogenicity Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 30/22, 87/65/43, 217/130/87 mg/kg/day for LD, MD, and HD, respectively Abbreviations: HD = high dose; LD = low dose; MD = mid dose

Clinical Signs

Compared to controls, HDM&Fs had CNS clinical signs of convulsions, tremors, salivation, and/or abnormal gait. In 2 HDMs and 3 HDFs, convulsions and/or tremors occurred prior to premature death, which led to dose reductions on day 130 and day 197, respectively (see mortality). After the dose was reduced to ≤87 mg/kg/day, no more clinical signs were observed.

Body Weights and Food Consumption

Compared to controls, viloxazine treatment caused dose-dependent decreases in body weight, weight gain, and/or food consumption in MDM&Fs and HDM&Fs. Body weight was decreased up to 7.7%, 8.4%, 12.5%, and 12.6% in MDMs, MDFs, HDMs, and HDFs, respectively (Figure 31). Cumulative weight gain was decreased by 5%, 7.3%, and 16.9% in HDMs, MDFs, and HDFs, respectively. Food consumption was decreased up to 11.0%, 18.3%, 9.4%, and 17.0% in MDMs, HDMs, MDFs, and HDFs, respectively. LD animals were not affected. It should be noted that the decreases were most apparent in the HD group early in the study when animals were treated at higher doses; after the second dose reduction, the decreases tended to resolve in HDM&Fs. Because the decreases in body weight were approximately in the range of the MTD (up to 12.6%), they are not considered to affect study quality or data interpretation.

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Figure 31. Body Weight Curve in the 2-Year Rat Carcinogenicity Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 30/22, 87/65/43, and 217/130/87 mg/kg/day, respectively

Ophthalmology

Compared to controls, there were no drug-related ophthalmic findings.

Hematology

At the end of the treatment period, standard hematology parameters were evaluated in blood samples collected from the first 10 animals/sex/group. Compared to controls, there were no drug- related changes in hematology parameters.

Gross Pathology

There were no drug-related abnormal gross pathology findings in either animals that died prematurely or those surviving until the scheduled necropsy. The incidences of all observed findings, including palpable mass, were comparable across all of the groups.

Histopathology

Peer review conducted: Yes Historical control provided for tumor incidence: Yes

Neoplastic

Compared to controls, there were no drug-related increases in the incidence of neoplastic tumors. Pairwise comparisons revealed a significant increase in the incidence of malignant cerebral glioma in MDMs relative to controls (4 of 65 [59] compared to 0 out of 65 [62] controls, Table 112). However, given the lack of significance in the trend analysis and the lack of similar findings in the HD group, this increase is not considered to be drug related.

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Table 112. Tumor Types with P-Values ≤0.05 for Pairwise Comparisons between the Treatment and Control Groups in the 2-Year Rat Carcinogenicity Study

Source: Excerpted from the statistical review of the Carcinogenicity Study Doses are presented as adjusted doses due to dose reductions during the study

Dr. Malick Mbodj from the Division of Biometrics conducted the statistical review. The following is an excerpt from Dr. Mbodj’s review:

Non-neoplastic

At the terminal necropsy, compared to controls, HDFs had an increased incidence of minimal to mild, focal, or multi-focal hepatocellular hypertrophy (10/44 compared to 3/51 controls). The Applicant considered this to be incidental. However, drug-induced hepatocellular hypertrophy and/or vacuolation were observed at comparable doses in previous 13-week and 18-month repeat-dose studies in rats of both sexes. In the general toxicology studies and carcinogenicity studies, females had higher drug exposure levels than males, which likely contributed to their increased incidence and/or severity of hepatocellular hypertrophy. Based on the similar findings of previous studies, it is considered to be drug related.

Toxicokinetics

On days 1 and 180, blood samples were collected from TK animals at 0.25, 0.5, 1, 3, 8, and 24 hours postdose18. TK parameters of viloxazine were analyzed. Two samples from control males on day 180 had quantifiable viloxazine concentrations. The values were very low and less than 0.3% of the Cmax in the LD group; therefore, they do not affect data interpretation. On both sampling days, after oral administration, viloxazine was rapidly absorbed and eliminated with Tmax values of 0.25 to 1 hour postdose and T1/2 values of 0.6 to 4.7 hours (Table 113). In general, the exposure levels were higher in females than males; however, the difference was generally less than 2-fold. In both sexes, the exposure (AUC) increased greater than dose proportionally. Due to dose reduction, the exposure levels were lower on day 180 relative to day

18 For control animals, samples were collected only at 0.5 hours postdose.

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1. After adjustment for dose reduction, the exposure levels were comparable between days 1 and 180, and there was no accumulation. Table 113. TK Parameters of Viloxazine in the 2-Year Rat Carcinogenicity Study

Source: Excerpted from the Applicant’s study reports Doses were reduced on day 130 from 217 and 87 mg/kg/day to 130 and 65 mg/kg/day in the HD and MD groups, respectively DN, dose-normalized Cmax and AUC parameters Abbreviations: AUC = area under the curve; HD = high dose; LD = low dose; MD = mid dose; T = time; TK = toxicokinetic 13.2.6.2. Twenty-six-Week Oral Gavage Carcinogenicity Study With Viloxazine in Transgenic rasH2 Mice Study no.: 812V-Tox2016-002 Study report location: EDR, SDN-1 Study initiation date: February 2, 2016 Conducting laboratory and location: (b) (4) GLP compliance: Yes Drug, lot #, and % purity: Viloxazine; 5003391/140016; 100.1% Prior Exec CAC Dose Concurrence: Y Basis for Dose Selection: Dose selection was based on a 5-day study at doses up to 434 mg/kg/day and a 4-week study at doses of 43, 130, and 173 mg/kg/day in Tg.rasH2 wild-type mice. CNS toxicity including convulsions were observed at doses ≥173 mg/kg/day and premature deaths occurred at 434 mg/kg/day, indicating that the MTD was exceeded at ≥173 mg/kg/day. No toxicities were observed at 43 mg/kg/day. Based on these findings, ECAC recommended doses of 0, 4.3, 13, and 43 mg/kg/day as the LD, MD, and HD, respectively.

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Key Findings

 Viloxazine did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks at oral doses of 4.3, 13, and 43 mg/kg/day. At the HD of 43 mg/kg/day, the exposure after 26 weeks of treatment is Cmax values of 3930 and 3100 ng/mL and AUCs of 20,400 and 12,700 ng*hour/mL in males and females, respectively.  Viloxazine at doses ≥4.3 mg/kg/day decreased body weight (up to 13%) and weight gain (up to 39%) in males. Females were generally not affected. Reviewer’s note: The Applicant conducted TK analysis in the wild-type mice on days 1 and 180. However, because the carcinogenicity study in the Tg.rasH2 mice is primarily used for hazard identification rather than risk assessment, the exposure multiples relative to the MRHD are not calculated. Table 114. Methods for 812V-Tox2016-002 Methods Details Doses: 0 (control), 4.3 (LD), 13 (MD), and 43 (HD) mg/kg/day Frequency of dosing: Once daily Number/sex/group: Main study: n=25/sex/group in Tg.rasH2 mice TK study: n=18/sex/group in wild-type mice, of which 9/sex/group were evaluated for liver histopathology after 60 days of recovery Positive control: n=20/sex Dose volume: 10 mL/kg Formulation/Vehicle: H2O Route of administration: ORAL Species: MOUSE Strain: CB6F1-TgN (RasH2) Age: Seven to eight weeks at treatment initiation Comment on study design and Positive control group was included, in which animals were conduct: treated intraperitoneally (IP) with urethane at 1000 mg/kg/day on days 1, 3, and 5. A TK analysis was conducted in wild-type mice. Dosing comments (dose adjustments There was no dose adjustment or early termination. or early termination): Dosing solution analysis: The concentrations of the dosing formulation were within the acceptable range. Source: summarized from the Applicant's study reports

Observations and Results

Mortality

Compared to controls, viloxazine did not affect survival in any of the treatment groups, when subjected to trend analysis or pairwise comparison. At the scheduled necropsy, there were 24 (96%), 23 (92%), 24 (96%), and 24 (96%) males and 24 (96%), 24 (96%), 25 (100%), and 24 (96%) females in the control, LD, MD, and HD groups, respectively. In the positive control group, 10 (50%) males and 8 (40%) females died prematurely between days 57 and 133. Moribund clinical signs included hypoactivity, dehydration, abdominal respiration, swelling in the thoracic region, distended abdomen, and ventral recumbent. Post

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mortem necropsy identified gross lesions in the lungs and spleen, which correlated with microscopic findings of adenoma and carcinoma in the lung and hemangioma and hemangiosarcoma in the spleen. Given the clear evidence of tumor-related mortality, the remaining positive control animals were terminated on day 133.

Clinical Signs

Compared to controls, viloxazine did not cause any abnormal clinical signs. Animals in the positive control group showed ataxia immediately postdose on treatment days. These clinical signs are expected, based on the anesthetic effects of urethane (Hara and Harris 2002).

Ophthalmology

Compared to controls, there were no viloxazine-related ophthalmic findings.

Body Weights and Food Consumption

During the treatment period, compared to controls, body weight was decreased by up to 12.1%, 8.8%, and 13.5% in LD, MD, and HD males, respectively; weight gain was decreased by up to 30%, 22%, and 39% in LD, MD, and HD males, respectively. Females were generally not affected during the treatment period, except for a slight decrease in cumulative weight gain in HDFs (<5%). At the end of the treatment period, compared to controls, body weight was significantly decreased in LDMs and HDMs; cumulative weight gain was decreased in LDMs, HDMs, and HDFs (Table 115). Food consumption was generally not affected by viloxazine. Table 115. Summary of Body Weight and Cumulative Weight Gain at the End of the Treatment Period in the 26-Week Carcinogenicity Study in Tg.rasH2 Mice Dose Body Weight on Day 180 (g) Cumulative Weight Gain (g) (mg/kg/day) Male Female Male Female 0 (Control) 34.37 23.92 12.18 6.23 4.3 (LD) 30.62* 23.37 8.6* 5.94 13 (MD) 31.40 23.41 9.48 5.99 43 (HD) 29.91* 22.90 7.4* 4.971 Source: Excerpted from the Applicant’s study reports 1 p≤0.01 Abbreviations: HD = high dose; LD = low dose; MD = mid dose

Hematology

At the scheduled necropsy, blood samples were collected from all surviving main study animals. Compared to the controls, slightly lower lymphocyte (4% to 17%) and higher neutrophil (33% to 39%) counts were observed in males at all doses. However, there was no clear dose relationship, and the values were within the historical control range at the test facility. Therefore, these changes are not considered to be drug related or adverse. Other hematology parameters were not affected.

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Gross Pathology

Compared to controls, the incidence of palpable mass was comparable across all groups. At the scheduled necropsy, HDFs had increased incidence of small thymus (9/25 compared to 1/25 controls) with correlative histopathology findings of thymus involution (7/25 HDFs relative to 1/25 control females). Thymus involution was also observed in other viloxazine-treated groups (see Histopathology). However, there was no clear dose relationship or other lesion in the thymus, and the thymus weight was not affected. Similar findings were not observed in the DRF study. Thymus involution is often associated with stress, particularly when the body weight was decreased in animals, rather than a direct drug effect on the thymus or immune system. Therefore, the toxicological significance of this finding appears to be limited. Animals in the positive control group had a high incidence of lung (100% incidence) and spleen (~80% incidence) lesions, which correlated with histopathology of adenoma and/or carcinoma in the lung and hemangioma and hemangiosarcoma in the spleen.

Histopathology

Peer review conducted: Yes Historical control provided for tumor incidence: Yes

Neoplastic

Compared to controls, there was no viloxazine-related increase in neoplastic findings at any dose. The positive control group had significant increases in the incidence of benign adenoma and malignant carcinoma in lung/bronchus and benign hemangioma and malignant hemangiosarcoma in the spleen in both sexes. Therefore, the Tg.rasH2 model used in this study is validated. Dr. Malick Mbodj from the Division of Biometrics conducted the statistical review. The following is an excerpt from Dr. Mbodj’s review:

Non-Neoplastic

Compared to controls, viloxazine at all doses increased the incidence of thymus involution in both sexes (Table 116). Involution of the thymus was characterized by reduced cortical and medullary cellularity, epithelia cysts, and increased prominence of epithelial cells. In the absence of other lesions in the thymus, these changes are likely due to aging and stress in the animals, 174 Integrated Review Template, version date 2019/10/16

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rather than a direct drug effect on the thymus (Greaves 2012). No other nonneoplastic lesions were observed. Table 116. Thymic Involution in the 26-Week Carcinogenicity Study in Tg.rasH2 Mice

Source: Excerpted from the Applicant’s study reports G1, control; G2, Low Dose; G3, Mid Dose; G4, High Dose

Special Histopathology Evaluation of the Liver

Wild-type TK animals were sacrificed at the end of the treatment (day 181) or after 2 months of recovery (day 240) (n=9/sex/group). The animals were examined for any gross lesions, and liver tissues were collected and evaluated for histopathology. At the scheduled necropsy (days 181 and 240), compared to controls, there were no viloxazine- related gross pathology findings or histopathology changes in the liver. Hepatocellular vacuolation was observed at comparable incidences in male groups, including the controls; therefore, they are not considered to be drug related.

Toxicokinetics

On days 1 and 180, blood samples were collected from wild-type TK animals at 0.25, 0.5, 1, 3, 8, and 24 hours postdose19. The TK parameters of viloxazine were analyzed. A single sample from a control male had a quantifiable viloxazine concentration; however, the value was low (0.74% of the Cmax in the LD group) and does not affect the data interpretation. On both sampling days, after oral administration, viloxazine was rapidly absorbed and eliminated with a Tmax of 0.25 hour postdose and a T1/2 of 0.7 to 2.3 hours. The exposure levels were generally comparable between males and females and increased slightly greater than dose proportionally. Drug exposure did not change significantly with repeat administration, and there was no accumulation (Table 117).

19 For the control TK group, blood samples were collected only at 0.25 hours postdose.

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Table 117. Summary of Viloxazine TK Parameters in the 26-Week Carcinogenicity Study in Tg.rasH2 Mice

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 4.3, 13, and 43 mg/kg/day, respectively Abbreviations: AUC = area under the curve; T = time; TK = toxicokinetic 13.2.7. Reproductive and Developmental Toxicology 13.2.7.1. Male and Female Fertility Study Study title: Viloxazine Hydrochloride: A Fertility and Reproductive Performance Study in Rat Study no.: 723-0038 Study report location: EDR, SDN-1 Conducting laboratory and (b) (4) location: GLP compliance: No (see overall comments) Drug, lot #, and % purity: Viloxazine; ADM 18420/72 and PDRM No. W0058; 99.3%

Key Findings

 Fertility parameters were not affected in male or female rats up to the maximum dose tested of 82 mg/kg/day.  At 82 mg/kg/day, viloxazine slightly decreased body weight, weight gain, and/or food consumption in female rats.  At 82 mg/kg/day, viloxazine decreased offspring viability with a correlative decrease in offspring weight.  Viloxazine was present in offspring plasma when measured during early lactation days, most likely transported via milk.  The NOAEL for male and female fertility is 82 mg/kg/day. The NOAEL for developmental toxicity in the offspring is 33 mg/kg/day.

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Table 118. Viloxazine Hydrochloride: A Fertility and Reproductive Performance Study in Rat Methods Methods Details Doses: 0 (control), 13 (LD), 33 (MD), and 82 (HD) mg/kg/day Frequency of dosing: Daily (via diet) Number/sex/group: n=15/dose group for males; n=30/dose group for females Dose volume: Not applicable Formulation/vehicle: Purina laboratory chow Route of administration: DIETARY Species: Rat Strain: Sprague-Dawley Comment on study design and This study adopted a one-generation, two-litter design. Briefly, conduct: male and female rats were treated with viloxazine via dietary intake. Male rats (n=15/group) were treated for 8 weeks prior to the first mating period; see below) and continued to receive dietary viloxazine treatment until completion of the second littering (a total of 22 weeks). Female rats (n=30/group) were treated for 2 weeks prior to the first mating with treated males. Subsequently, 15 females per dose group were evaluated via cesarean section on gestation day (GD) 13. The remaining 15 females per dose group were allowed to deliver the first litter and mated again with the treated males 2 to 3 weeks after weaning of the first litter to produce a second litter. During this period, females continued to receive dietary viloxazine treatment until the last week of lactation of the second litter (a total of 13 weeks). At the terminal necropsy, all sires and dams were evaluated for gross pathology; in addition, 2 male and 2 female pups in each of the second litter were examined for gross pathology. Dosing solution analysis: The stability and concentration of viloxazine in the diet were confirmed to be within the acceptable range. Source: summarized from the Applicant's study reports

Observations and Results

Mortality

There were no drug-related premature deaths in the study.

Clinical Signs

There were no abnormal clinical signs in the study.

Body Weight and Food Consumption

Compared to controls, body weight and weight gain were slightly decreased in HDMs and sometimes in LDMs throughout the study. The decreases were generally mild (≤~5%) without clear correlative changes in food consumption; therefore, they are not considered to be adverse. Compared to controls, HDFs had weight loss during the first two weeks (up to 2.2 g weight loss) after treatment initiation, which correlated with decreased food consumption (up to 20%). HDFs also had decreased weight gain during the last week of the second gestation period (~7%), which also correlated with decreased food consumption (~10%). After delivery of the second litter, the

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body weight gain was comparable across all groups during the lactation period. Given the transient nature and small magnitude, the slight decreases in body weight did not affect the overall health of the animal and are not considered to be adverse. Reviewer’s note: During the mating period, males received the same diet as females, in which the viloxazine concentration was adjusted based on female body weights. Because females generally weigh less than males, it is estimated that the actual viloxazine doses administered to the males were 10% to 30% lower than the designated values. However, because the mating period was only 2 weeks each, whereas males received adequate viloxazine doses during the rest of the 22-week treatment period, it is unlikely that the decreased viloxazine doses during the mating period would significantly affect the study outcome. Similarly, for female rats, because body weights were not measured during the first lactational period, no dose adjustment was made for females when their body weights decreased due to parturition and their food consumption increased to support lactation. It is estimated that the viloxazine doses in females during the first lactation period increased by 50% to 75%. The increases in viloxazine doses do not impact study interpretation because they did not adversely affect maternal health during this period.

Fertility and Pregnancy Parameters

Compared to controls, male or female fertility was not affected by viloxazine; the fertility and gestation index were comparable across all groups, including the controls (Table 119). In addition, cesarean evaluation in females on gestation day (GD) 13 did not identify any drug- related effects. The number of viable embryos, resorption, implantation sites, corpora lutea, and pre- and postimplantation loss were comparable across all of the groups. Table 119. Male and Female Fertility Index in the Rat Fertility Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 13, 33, and 82 mg/kg/day, respectively

Viability of Offspring

Compared to controls, pup viability at birth and on lactation day (LacD) 4 was comparable across all groups; however, from LacD 4 (when all litters were culled to 10 pups per litter) to LD 21 (weaning), offspring viability (lactation index) was significantly decreased in the HD group

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(30%, Table 120) for the first littering period, which also correlated with decreased offspring body weight (up to 21%, Table 121). The deaths of offspring primarily occurred between LacDs 8 and 14, during which 33 pups in 7 litters in the HD group died compared to 8 pups in 3 litters in the control group. The Applicant stated that the period of the greatest loss coincided with a 6.5-hour power outage, during which the temperature and humidity in the room gradually increased to over 80°F and 50%, respectively. However, given that the power outage affected all groups in the same room, the decreases in offspring viability in the HD group are most likely drug related, although the data could not distinguish between a direct drug effect on the offspring and an indirect drug effect due to deficits in maternal care. Table 120. Drug-Related Decreases in Offspring Viability/Lactation Index in the Rat Fertility Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 13, 33, and 82 mg/kg/day, respectively * p<0.05, ** p<0.01 compared to controls Table 121. Drug-Related Decreases in Offspring Body Weight in the Rat Fertility Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 13, 33, and 82 mg/kg/day, respectively Adj 1, adjusted for litter size; ** p<0.01 compared to controls

Necropsy

At the end of the second littering period, all F0 males and females as well as 2 male and 2 female pups from each litter were evaluated for gross pathology. Compared to controls, there were no drug-related gross pathology findings.

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Key Findings

 Viloxazine, at doses up to 82 mg/kg/day, did not cause maternal toxicity.  At 82 mg/kg/day, viloxazine caused fetal toxicities, including increased early and late resorption and increased number of small fetuses with delayed development.  At 82 mg/kg/day, possible drug-related fetal malformations or anomalies were observed at relatively low incidences, including a single fetus with craniorachischisis (severe neural tube defect), 2 fetuses from a single litter with darkening of the lining of the third ventricle (potentially associated with hydranencephaly), and 2 fetuses from a single litter with missing cervical vertebrae.  The NOAEL for maternal toxicity is 82 mg/kg/day. The NOAEL for embryofetal toxicity and malformation is 33 mg/kg/day. Reviewer’s note: At 82 mg/kg/day, low incidences of fetal malformation or anomalies, such as craniorachischisis, internal hydrocephalus, and missing vertebrae, were observed in single dams in the HD group. These changes could be spontaneous. However, in the absence of historical control data, a drug effect could not be completely excluded. Because the study is a legacy study without full GLP compliance, considering the uncertainty of the overall evidence, The NOAEL for fetal malformation is conservatively set at 33 mg/kg/day. Table 124. Viloxazine Hydrochloride: A Teratogenic Potential Study in Rats–Oral Methods Methods Details Doses: 0 (control), 13 (LD), 33 (MD), and 82 (HD) mg/kg/day20 Frequency of dosing: Once daily Number/sex/group: n=23/group Dose volume: 5 mL/kg Formulation/vehicle: H2O Route of administration: ORAL GAVAGE Species: Rat Strain: Not specified in the study report Comment on study design Pregnant rats were orally treated with viloxazine at 0, 13, 33, and and conduct: 82 mg/kg/day from GDs 6 to 15, which is slightly shorter than GDs 6 to 17, typically used in current studies. However, it is adequate to cover the period of organogenesis in rats. Cesarean evaluation was conducted on GD 20. Dosing solution analysis: The stability and concentration of viloxazine were confirmed to be acceptable for the study duration. Source: summarized from the Applicant's study reports

Observations and Results

F0 Dams

Mortality

There were no premature deaths in the study.

20 Doses are presented as free base-equivalent doses. The original doses of 0, 15, 38, and 95 mg/kg/day viloxazine hydrochloride are converted to free base-equivalent doses using a correction factor of 0.867.

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Clinical Signs

There were no drug-related abnormal clinical signs. During the study, 3 dams were slightly injured due to repeated gavage procedure but recovered within 1 week.

Body Weight and Food Consumption

Compared to controls, there were no drug-related changes in body weight or weight gain. Food consumption was not measured; however, because there were no drug effects on body weight, weight gain, or any abnormal clinical signs, the animals appeared healthy throughout the study; and the lack of food consumption data did not affect data interpretation.

Cesarean Section Data

Two, two, four, and two females in the control, LD, MD, and HD groups were not pregnant. In addition, one dam each in the control (no. 1211) and MD (no. 3213) groups had no viable fetuses. Given the comparable incidences and lack of a clear dose relationship, these are not considered to be drug related. For comparison of group mean values, 20, 21, 18, and 21 dams were evaluated in the control, LD, MD, and HD groups, respectively. Compared to controls, the HD group had increased mean number of corpora lutea, implantation sites, and early and late resorptions (Table 125). It should be noted that due to the increases in the absolute number of corpora lutea and implantation sites, the number of viable fetuses per dam was not decreased at the HD; however, after adjustment for the number of corpora lutea and implantation sites, the percentage of early and late resorption was increased at the HD, suggesting a potential drug-related embryotoxicity. Table 125. Drug-Related Changes in Cesarean Parameters in the Rat Embryo-Fetal Developmental Toxicity Study Implantation Early Corpora Lutea Sites Viable Fetus Resorption Late Resorption Control 14.7 261 (12.8) 12.4 13 (5 %) 0 (0%) LD 15.9 287 (13.7) 13.1 14 (4.9%) 0 (0%) MD 16.1 256 (14.1) 13.5 14 (5.5%) 0 (0%) HD 17.9* 313 (14.8*) 13.1 33 (10.5%)* 5 (1.6%)* Source: Modified/reformatted based on the data in the Applicant’s study reports Values are mean numbers per dam/litter * p<0.05 compared to controls Abbreviations: HD = high dose; LD = low dose; MD = mid dose

Necropsy/Histopathology

At the scheduled necropsy, there were no drug-related abnormal gross pathology findings. Histopathology evaluation in the dams was not conducted.

F1 Offspring

Terminal Observations

Compared to controls, the HD group had an increased incidence of small fetuses (<3.2 g body weight and 0.5 g less in body weight than the rest of the same litter, mean fetal weight in the HD

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group was 3.86 g) when counted both by litter and by fetus (Table 126). These fetuses were slightly delayed in development, as evidenced by delayed ossification of the sternum. In addition, the crown-rump measurements (a measurement of fetal length and size) revealed a trend towards larger fetuses in the LD and MD groups and smaller fetuses in the HD group relative to the controls, although the difference did not reach statistical significance (Table 126). Other parameters, such as the fetal sex ratio, were not affected. Table 126. Drug-Related External Fetal Observations in the Rat Embryo-Fetal Developmental Toxicity Study Litters with Number of Fetal Weight (g, Crown-Rump Measurement Small Fetuses Small Fetuses Adjusted for Litter Size) (mm, Adjusted for Litter Size) Control 5 5 3.95 37.12 LD 1 1 4.12 37.67 MD 2 2 4.18* 37.77 HD 7a 19b,c 3.86 36.59 Source: Modified/reformatted based on the data in the Applicant’s study reports a p<0.05 compared to controls b Includes 1 litter of 11 fetuses (dam no. 4222), in which 8 were small. One of the small fetuses in this litter had craniorachischisis c Includes 1 fetus with a placenta superimposed or fused with another placenta to a normal-size fetus Abbreviations: HD = high dose; LD = low dose; MD = mid dose

Fetal Malformations/Variations (External, Visceral, Skeletal)

External

One HD dam (No. 4222) had 1 fetus (from a litter of 11) with craniorachischisis (a severe type of neural tube defect, in which both the brain and spinal cord remain open). No historical data were provided in the study report; based on current historical control data at the time of this review, craniorachischisis is a rare finding. The Applicant considered it to be incidental because there were no correlative malformations or anomalies (such as encephalocele, exencephaly, or spina bifida). Although this is a reasonable argument, given the visceral and skeletal findings in the HD group, a drug effect could not be completely excluded.

Visceral

Compared to the control group, the MD and HD groups had slight increases in the incidence of renal pelvic dilation. HD group had a single incidence of slightly distended bladder (Table 127). These are commonly observed fetal variations. Given the low incidence, they are not considered to be adverse. Two fetuses from a single HD dam had darkening of the lining of the third ventricle (Table 127), a condition reported to be associated with internal hydrocephalus (Richardson and Hogan 1946). Therefore, a potential drug-related effect at the HD could not be excluded.

Skeletal

Compared to controls, 2 fetuses from a single HD litter (dam no. 4223) had only 6 cervical vertebrae (missing the seventh vertebra, a potential skeletal malformation). A potential drug- related effect could not be excluded. In addition, HD fetuses had an increased incidence of delayed ossification of the sternebrae, a nonadverse variation likely due to delayed fetal development.

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Methods Details Comment on study design The study also included a dose range-finding phase (part I), in and conduct: which pregnant rabbits were orally treated with viloxazine at 0, 43, 87, 130, and 217 mg/kg/day (n=7/group) from GD 6 to 18. Cesarean evaluation was conducted on GD 29. Viloxazine did not cause any maternal or fetal toxicity at 43 mg/kg/day. At 87 and 130 mg/kg/day, viloxazine decreased maternal food consumption (up to 37%) with no fetal toxicity. At 217 mg/kg/day, viloxazine caused maternal weight loss (-0.12 kg compared to +0.12 kg in controls) and decreased food consumption (56.2%). At this maternally toxic dose, viloxazine also caused increased post-implantation loss (39%). These data suggest that MTD was exceeded at 217 mg/kg/day, whereas the maternal toxicities of decreased body weight and food consumption at 130 mg/kg/day were tolerated. Therefore, 130 mg/kg/day was selected as the high dose for the definitive phase (part II). Dosing solution analysis: The concentrations of the dosing formulation were within the acceptable range. Source: summarized from the Applicant's study reports

Observations and Results

F0 Dams

Mortality

There were no drug-related premature deaths in the study. One, two, zero, and one rabbit aborted in the control, LD, MD, and HD groups, respectively. One of the 2 LD animals (No. 3566) that aborted also died on GD 25; a post mortem evaluation did not identify any cause. Because there was no mortality observed at higher doses, this death is considered to be incidental.

Clinical Signs

During the treatment period, compared to controls, 1 HD animal showed clinical signs of hyperpnea and abduction of fore- and hind-limbs postdose on GDs 13 and 16 (treatment days 8 and 11). Considering the low incidence, transient nature, and no effect on the general health of the animal, this finding is not considered to be adverse. No other drug-related clinical signs were observed.

Body Weight and Food Consumption

During the treatment period (GD 6 to 18), compared to controls, body weight gain was dose- dependently decreased at all doses. The decreases were more profound in the MD (no weight gain) and HD (weight loss) groups, and correlated with decreased food consumption (up to ~45% in the MD and HD groups), and were reversible during the treatment-free period (GD 18 to 29, Table 129).

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Table 129. Drug-Related Decreased in Body Weight Gain in the Rabbit Embryo-Fetal Developmental Toxicity Study Dose (mg/kg/day) 0 (Control) 43 (LD) 87 (MD) 130 (HD) Body weight on GD 6 (kg) 3.2 3.18 3.14 3.16 Body weight on GD 18 (kg) 3.33 3.25 3.14 3.14 Body weight on GD 29 (kg) 3.41 3.37 3.30 3.27 Weight gain during treatment period 0.13 0.07 0.0 -0.02 (kg, GD 6-18) Weight gain during treatment free 0.08 0.12 0.16 0.13 period (kg, GD 18-29) Source: Modified/reformatted based on the data in the Applicant’s study reports Abbreviations: GD = gestation day; HD = high dose; LD = low dose; MD = mid dose

Cesarean Section Data

At the scheduled cesarean, compared to controls, there were no drug-related changes in maternal reproductive parameters. The gravid uterine weight, number of corpora lutea, implantations, early and late resorptions, and pre- and post-implantation loss were comparable across all groups, including the control group.

Necropsy/ Histopathology

At the scheduled cesarean, compared to controls, there were no drug-related gross pathology findings in the dams.

Toxicokinetics

On GDs 6 and 18, blood samples were collected at 0.25, 0.5, 1, 3, 8, and 24 hours postdose from TK animals21. The TK parameters of viloxazine were analyzed.

On both sampling days, after oral administration, viloxazine was rapidly absorbed, with a Tmax of 0.25 to 1 hour postdose; and quickly eliminated, with a T1/2 of 1.8 to 3.6 hours. The exposure (AUC) to viloxazine increased greater than dose proportionally. The exposure profiles were largely comparable between GD 6 and GD 18, and there was no significant accumulation.

21 For control TK animals, blood samples were collected only at 0.25 hours postdose.

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Table 130. Toxicokinetic Parameters of Viloxazine in the Rabbit Embryo-Fetal Developmental Toxicity Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 43, 87, and 130 mg/kg/day, respectively Abbreviations: AUC = area under the curve; GD = gestation day; T = time

F1 Offspring

Terminal Observations

Compared to controls, there was a slight but not statistically significant decrease in mean fetal weight in the HD group (7%), which correlated with the decrease in maternal weight gain during the gestational treatment period. Given the small magnitude and lack of other adverse fetal findings, it is not considered to be adverse. Other parameters were not affected, including the average number of fetuses, live fetuses, and sex ratio.

Fetal Malformations/ Variations (External, Visceral, Skeletal)

External

Compared to controls, there was no drug-related external fetal malformation or variation. A single fetus in the HD group had a moderately flexed left forelimb at the wrist (fetal incidence/group of 0.7%). However, the incidence value was within the historical control range at the test facility (0.81%); therefore, it is not considered to be drug related.

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Visceral

Compared to controls, there was no drug-related visceral malformation.

Skeletal

Compared to controls, there was no drug-related skeletal malformation. A slight increase in the incidence of incomplete ossification of the second sternebrae was observed in HD fetuses (4 fetuses in 4 litters, compared to 2 fetuses in 1 litter in the controls), which correlated with slightly decreased fetal weight in this group. They are not considered to be adverse. 13.2.7.3. Pre- and Post-natal Developmental Toxicity Study title: Study of Effects of Orally Administered SPN-812V on Pre- and Post-natal Development, including Maternal Function in Wistar Rats Study no.: 821V-Tox2017-017 Study report location: EDR, SDN-1 Conducting laboratory and location: (b) (4) GLP compliance: Yes Drug, lot #, and % purity: Viloxazine; 5002946/130032; 100.5% Enhanced PPND Study:N

Key Findings

 Viloxazine, at 217 mg/kg/day, caused premature deaths in 4/20 dams and led to a dosing holiday between GD 20 to 23 in 9 dams.  Viloxazine, at 217 mg/kg/day, caused significant decreases in maternal body weight, weight gain, and food consumption during the gestation and lactation periods. At 87 mg/kg/day, maternal body weight gain was also decreased during the gestation period.  Viloxazine, at ≥87 mg/kg/day, reduced the live birth rate and decreased offspring viability during the early lactation period (day 1 to day 4).  Viloxazine, at ≥87 mg/kg/day, caused delayed development in the offspring during the pre-weaning period. At 217 mg/kg/day, viloxazine also caused delayed growth and sexual maturation in the offspring during the postweaning period.  Viloxazine, at doses up to 217 mg/kg/day, did not affect the neurobehavioral parameters, including learning and memory, or the reproductive capacity of the offspring.  The NOAEL for maternal toxicity and developmental toxicity is 43 mg/kg/day. The corresponding maternal exposure levels are a Cmax of 3600 ng/mL and an AUC of 7880 ng*hour/mL on lactation day 20.

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Table 131. Study of Effects of Orally Administered Viloxazine on Pre- and Post-natal Development, Including Maternal Function in Wistar Rats Methods Methods Details Doses: 0 (control), 43 (LD), 87 (MD), and 217 (HD) mg/kg/day22 Frequency of dosing: Once daily Number/sex/group: Main study: n=20/dose group for main study. TK: n=9/ dose group for viloxazine-treated groups and n=5 for the control group. Dose volume: 10 mL/kg Formulation/vehicle: H2O Route of administration: ORAL GAVAGE Species: Rat Strain: Wistar Comment on study design and Pregnant rats were orally treated with viloxazine at 0, 43, 87, and conduct: 217 mg/kg/day from GD 6 to weaning (lactation day 20). Parameters evaluated include: for F0 dams: mortality, clinical signs, body weight and food consumption, parturition, lactation, and gross pathology at scheduled necropsy; for F1 generation: viability, clinical signs, body weight and food consumption, sexual maturation, neurobehavioral assessment (sensory and motor activity, learning and memory), reproductive capacity, and gross pathology. Dosing solution analysis: The concentration and stability of the dosing formulation were within the acceptable range. Source: summarized from the Applicant's study reports

Observations and Results

F0 Dams

Mortality and Clinical Signs

During the gestation period, 4 HD dams died prematurely during GD 20 to 22; only one of these dams was observed with moribund signs of recumbency (Table 132). A post mortem necropsy showed non-glandular stomach thinning in 3 of the 4 dams, which is more likely a secondary change due to the general poor health of the animal, rather than the direct cause of death. Nevertheless, given the multiple incidences at HD, these deaths are considered to be drug related. Due to the premature deaths, dosing was paused for the remaining 11 dams that had not yet littered (GD 20 to 23) and resumed following littering. Of the 16 surviving dams, 5 dams littered before dosing was paused and 9 dams littered after dosing suspension; 2 females were not pregnant. There were no drug-related clinical signs in the dams that survived until littering and scheduled necropsy.

22 Doses are presented as free base-equivalent doses. The original doses of 0, 50, 100, and 250 mg/kg/day viloxazine hydrochloride are converted to free base-equivalent doses using a correction factor of 0.867.

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Table 132. Drug-Related Premature Deaths in the Rat Pre- and Post-natal Developmental Toxicity Study

Source: Excerpted from the Applicant’s study reports Abbreviations: GD = gestation day

Body Weight and Food Consumption

During gestation, compared to controls, viloxazine caused dose-dependent decreases in maternal body weight, weight gain, and food consumption. The decreases were most profound in the HD group during the first 3 days after treatment initiation (up to 8%, 69%, and 23% in body weight, weight gain, and food consumption, respectively, Table 133). Weight gain in the MD group was also decreased (by 50.44%). Table 133. Drug-Related Decreases in Maternal Body Weight, Weight Gain, and Food Consumption in the Rat Pre- and Post-natal Developmental Toxicity Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 43, 87, and 217 mg/kg/day, respectively * p<0.01 Abbreviations: GD = gestation day

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During the lactation period, compared to controls, maternal body weight and weight gain were decreased in the HD group (by 7% to 9% and 21% to 120%, respectively), which correlated with decreased food consumption (22% to 26%). The LD and MD groups were generally not affected during the lactation period.

Parturition and Litter Observations

At parturition, pregnancy was confirmed in 16 (80%), 20 (100%), 20 (100%), and 18 (90%) out of the 20 mated females in the control, LD, MD, and HD group, respectively. Compared to controls, MD and HD groups had increased number of dead pups (16 and 20 in the MD and HD groups, respectively, compared to 0 in the control group). The HD group had decreased gestation index (92.9% compared to 100% in the control group), due to 1 HD dam delivering all dead pups (3 pups in total) on GD 24 after 3 days of dosing holiday. In addition, the HD group had increased post-implantation loss (32.4%, compared to 11.5% in controls); this value was also out of the historical control range at the test facility. From lactation days (LacDs) 0 to 4, compared to the control group, the MD and HD groups had increased number of total litter loss (3 in both the MD and HD groups, compared to 0 in the control group), which resulted in a lower survival index (80.8% and 86.5% in the MD and HD groups, respectively, compared to 97.8% in the control group). In addition, compared to controls, HD pups had decreased body weight (up to 32%) during the lactation period (Table 134). Values in the MD and HD groups were also out of the historical control range. Because maternal nursing behavior was not specifically evaluated in the study, it is unclear whether the decreases in pup survivability were due to direct drug effects on the pups via lactational exposure or indirect drug effects from deficits in maternal care. The LD group was not affected. In addition, compared to the controls, HD pups had decreased body weight (by up to 32%) during the lactation period. Table 134. Drug-Related Decreases in Offspring Survivability in the Rat Pre- and Post-natal Developmental Toxicity Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 43, 87, and 217 mg/kg/day, respectively * p<0.01

Gross Pathology

At the scheduled necropsy, there were no drug-related gross pathology findings in the dam or in the pups that were culled on LacD 4.

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F1 Generation

Mortality and Clinical Signs

Compared to controls, there were no drug-related changes in offspring mortality and clinical signs.

Post-natal Development

During the preweaning period, compared to controls, there were dose-dependent delays in offspring development, which correlated with decreased pup body weight (up to 8%, 13%, and 32% in the LD, MD, and HD groups, respectively, relative to the control group). Delayed growth/development was most profound in the HD group (Table 135). Table 135. Drug-related Delay in Offspring Growth and Development in the Rat Pre- and Post-natal Developmental Toxicity Study Dose Postnatal Day Control LD MD HD % Pups Reached Pinna Detachment/Litter 2 27.7 16.9 11.8* 8.3* 3 58.2 46.7 51.1 29.2* 4 100 100 100 100 % Pups Reached Incision Eruption/Litter 11 81.4 82.2 88.0 62.2* 12 100 100 100 81.0 13-14 NA NA NA 100 % Pups Reached Eye Opening/Litter 14 16.4 4.3* 5.9 0* 15 43.6 26.3* 22.7* 15.2* 16 77.3 74.9 81.8 49.1* 17 100 100 100 95.6 18 NA NA NA 100 % Pups Reached Testes Descent/Litter 19 20.3 30.8 12.3 5.0* 20 100 100 100 73.5* 21 NA NA NA 100 Source: Modified/reformatted based on the data in the Applicant’s study reports * p<0.05 compared to controls Abbreviations: HD = high dose; LD = low dose; MD = mid dose During the postweaning period, compared to controls, HD offspring had decreased body weight (up to 19% to postweaning day 22) and decreased weight gain (up to 20.1% to post-weaning day 8), which correlated with decreased food consumption (up to 14.5%).

Sexual Maturation

Compared to controls, HD offspring had delayed preputial separation (49 days compared to 46 days for the controls) and vaginal opening (36 days compared to 35 days for the controls). This delay is likely secondary to delayed growth rather than a direct drug effect, because the body weight at the time the offspring reached sexual maturation was similar across all groups.

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Neurobehavioral Assessment

Compared to controls, there were no drug-related changes in sensory observations, motor activity, or learning and memory (M-Watermaze performance) in the offspring.

Reproductive Capacity

Compared to controls, there were no drug-related changes in reproductive performance in the offspring. The precoital interval, mating and fertility indices, and litter data (litter size, live birth index, and survival index) were comparable across all groups. Maternal weight, weight gain, and food consumption during the gestation period were comparable.

Gross Pathology

At the scheduled necropsy, compared to controls, there were no drug-related findings in F1 dams or F2 offspring.

Toxicokinetics and Lactation (Exposures)

On GD 6, GD 20, and LacD 20, blood samples were collected at 0.25, 0.5, 1, 3, 8, and 24 hours postdose from the F0 dams.23 A TK analysis of viloxazine was conducted.

On all three sampling days, after oral administration, viloxazine was rapidly absorbed with Tmax values of 0.25 to 0.5 hours. The T1/2 was 1.7 to 5.1 hours. The exposure to viloxazine increased dose proportionally. There was no significant accumulation after repeat dosing and the exposure profiles were generally comparable on all three sampling days (Table 136).

23 Control samples were collected only at 0.25 hour postdose.

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Table 136. Toxicokinetic Parameters of Viloxazine in the Rat Pre- and Post-natal Developmental Toxicity Study

Source: Excerpted from the Applicant’s study reports Doses are presented based on viloxazine hydrochloride; the free base-equivalent doses are 43, 87, and 217 mg/kg/day Abbreviations: GD = gestation day; LD = lactation day

Viloxazine Hydrochloride: A Peri-natal and Post-natal Study in Rats (Study 723-0033, Non- GLP)24

Pregnant Sprague-Dawley rats were orally treated with viloxazine from GD 15 throughout lactation until weaning, at doses of 0 (water control), 13 (LD), 33 (MD), and 82 (HD) mg/kg/day (n=22/group for the control, LD, and HD groups; n=15 for the MD group). The maternal parameters evaluated included general health, body weight, weight gain, and parturition. The developmental parameters evaluated included offspring body weight and viability throughout the lactation period. In addition, at the scheduled necropsy, gross pathology was evaluated in the dams and offspring (two pups/sex/group). Maternal Toxicity: Compared to controls, viloxazine at doses up to 82 mg/kg/day did not cause any significant maternal toxicity. A slight but nonsignificant decrease in maternal weight was observed at 82 mg/kg/day during the last week of lactation (~6%). Given the small magnitude, it is not considered to be adverse. The LD and MD groups were not affected. Developmental Toxicity: Compared to controls, viloxazine, at 82 mg/kg/day, caused decreased body weight in the offspring (7% to 12%); the decreases in pup body weight persisted throughout the lactation period. No other developmental toxicities were observed. The LD and MD groups were not affected. Based on the above findings, the NOAEL for maternal toxicity is 82 mg/kg/day and the NOAEL for developmental toxicity is 33 mg/kg/day.

24 This is an abbreviated legacy study conducted in 1975, prior to implementation of GLP regulations, in which limited parameters were evaluated in the offspring.

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Viloxazine Hydrochloride: A Peri-natal and Post-natal Study in Mice (Study 723-0044, Non- GLP)25

Pregnant Swiss–Webster mice were orally treated with viloxazine at doses of 0 (water control, Group 1/G1), 13 (LD, G2), 33 (MD, G3), and 82 (HD, G4) mg/kg/day from GD 13 throughout lactation until weaning (n=22/group), or at 82 mg/kg/day (HD, G5, n=22) from GD 13 until parturition or from parturition until weaning (HD, G6, n=22). The maternal parameters evaluated included general health, body weight, parturition, and nursing behavior. The developmental parameters evaluated included offspring body weight and viability. In addition, at the scheduled necropsy, gross pathology was evaluated in the dams and offspring (two pups/sex/group).

Maternal Toxicity: Compared to controls, at 82 mg/kg/day, there was increased mortality in the dams when they were treated during the late gestation stage (5/22 deaths in each of the G4 and G5 groups, compared to 0/22 in the control group and 1/22 in G6 (treated at the same dose but only during the lactation stage). The causes of death could not be determined. Post mortem necropsy did not identify any abnormal findings except for glycogen depletion in the liver, which is possibly related to the slight decreases in maternal weight (up to 6% in G4 relative to controls), rather than a cause of death. More perplexing is that all deaths occurred during the lactation period, despite the fact that animals in the G5 group did not receive viloxazine during that period. Nevertheless, considering the large increases in the maternal death rate in G4 and G5, it is reasonable to conclude that viloxazine at 82 mg/kg/day during the late gestation stage (after GD 13), but not the lactation stage, increased the risk of maternal death. LD or MD animals were not affected. It should be noted that in other repeat-dose studies in mice, doses up to 130 mg/kg/day were generally tolerated. Drug effects at doses comparable to 82 mg/kg/day were limited to CNS hypoactivity and impaired gait. Therefore, the mortality observed in the current study was possibly due to increased sensitivity to drug effects during pregnancy. Developmental Toxicity: Compared to controls, at 82 mg/kg/day, the offspring body weight was significantly decreased in the G4 and G6 groups (11.4% and 12.9%, respectively), in which the dams were treated throughout the lactation period, but not in the G5 group, in which the dams were treated at the same dose but only during the gestation period. Because no significant difference in maternal nursing behavior was observed, the decreases in offspring body weight during the lactation period are most likely a direct drug effect via lactational exposure. The LD and MD groups were not affected. Based on the findings, the NOAEL for both maternal and developmental toxicity is 33 mg/kg/day.

25 This is a legacy study conducted in 1976, prior to implementation of GLP regulations. This is an abbreviated study, in which limited parameters were evaluated in the offspring

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13.2.7.4. Juvenile Animal Study Study title: Eight-Week Oral Rat Juvenile Toxicity and Toxicokinetic Study with Recovery Evaluation Study no.: 812V-Tox2012-001 Study report location: EDR, SDN-1 Conducting laboratory and location: (b) (4) Duration: 8 Duration units: Weeks GLP compliance: Yes Drug, lot #, and % purity: Viloxazine; 110011 (L-8340-101-001); 99.9%

Key Findings

 A possible drug-related premature death occurred at 217 mg/kg/day.  At 217 mg/kg/day, viloxazine caused ptosis in both sexes and transient decreases in motor activity in females. Both effects were reversible.  At ≥130 mg/kg/day, viloxazine caused dose-dependent decreases in body weight, weight gain, and food consumption, which were reversible after recovery. The decreases at 130 mg/kg/day were generally mild and not considered to be adverse.  Viloxazine, at doses up to 217 mg/kg/day, did not affect sexual maturation, reproductive capacity, or learning and memory in juvenile rats.  The NOAEL in juvenile rats is 130 mg/kg/day. After 8 weeks of repeat treatment, the corresponding exposure levels are Cmax values of 2760 and 5020 ng/mL and AUCs of 10,500 and 28,100 ng*hour/mL in males and females, respectively. Table 137. 8-Week Oral Rat Juvenile Toxicity and Toxicokinetic Study with Recovery Evaluation Methods Methods Details Doses: 0 (control), 43 (LD), 130 (MD), and 217 (HD) mg/kg/day26 Frequency of dosing: Once daily Number/sex/group: Main study (subset A): n=15/sex/group Recovery study (subset B): n=20/sex/group TK study (subset C): n=18/sex for the LD, MD, and HD groups; n=3 for the control group Dose volume: 10 mL/kg Formulation/vehicle: H2O Route of administration: ORAL GAVAGE Species: Rat Strain: Sprague–Dawley (Crl:CD (SD)) Age at start of experiment: PND 23 Period of development Juvenile rats were treated from PND 23 to PND 79, followed by an studied: 8-week recovery period

26 Doses are presented as free base-equivalent doses. The original doses of 0, 50, 150, and 250 mg/kg/day viloxazine hydrochloride are converted to free base-equivalent doses using a correction factor of 0.867

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Methods Details Comment on study design Dose selection was based on a 17-day DRF study (Study 812V- and conduct: Tox2010-018), in which juvenile rats were orally treated with viloxazine from PND 23 to PND 40 at doses of 0, 21.7, 43, 87, 217, and 434 mg/kg/day. No significant drug-related toxicities were observed at doses up to 217 mg/kg/day. At 434 mg/kg/day, viloxazine caused transient hypoactivity, significant decreases in body weight (˃24%), weight gain (~25%), and food consumption (>15%), and increases in liver weight (~25%). In addition, the absolute and relative weights of lymphoid organs (spleen and thymus) were decreased (~20% to 32%). Given the relatively large magnitude of decreases in body weight and weight gain, 434 mg/kg/day likely exceeded the MTD. In addition, in a previous 3- month general toxicity study in adult rats, doses up to 217 mg/kg/day were tolerated. Drug-related findings were mainly limited to increased liver weight with histopathology of hepatocellular hypertrophy and vacuolation. Based on these findings, 217 mg/kg/day was selected as the high dose in the definitive study. Parameters and key Mortality, clinical signs, body weight, weight gain, food endpoints evaluated: consumption, ophthalmology, growth and sexual maturation, neurobehavioral assessment (FOB, motor and sensory activity, learning and memory), clinical pathology, IGF-1, organ weights, gross pathology and histopathology, and reproductive capacity. Dosing solution analysis: The concentration of the dosing formulation was within the acceptable range. Source: summarized from the Applicant's study reports

Observations and Results

Mortality

One possible drug-related death occurred in HDM (No. 2152) on postnatal day (PND) 28. Prior to death, this animal had clinical signs of mild dehydration, ptosis, decreased motor activity, loss of righting reflex, tremors, cold to touch, tachypnea, and urine-stained abdominal fur. A post mortem necropsy did not identify any abnormal findings. The Applicant considered it to be incidental; however, because a similar clinical sign (ptosis) was observed in other HD animals in this study or at the same dose in previous studies in adult rat (decreased motor activity, ), a potential drug-related effect could not be excluded. Three incidental premature deaths occurred in 2 MDMs (Nos. 2208 and 2211) and 1 MDF (No. 2395). Animal 2208 (MDM) was euthanized on PND 66 due to a lesion in the left eye, which was first identified on PND 28 and continued to exacerbate. Given the unilateral nature of the eye lesion, it is not considered to be drug-related. Animal 2211 (MDM) was euthanized on PND 45 due to significant body weight loss. A post mortem necropsy identified urinary tract lesions and build-up of calculi in the bladder, which is a known but rare spontaneous finding in this strain of rat; therefore, it is not considered to be drug-related. Animal 2395 (MDF) was euthanized after it delivered a litter due to a mistimed pregnancy. Other than the mistimed pregnancy, there were no abnormal findings in this female; all the pups appeared normal. Therefore, there is no drug-related finding in this female.

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Clinical Signs

During the treatment period, compared to controls, ptosis occurred dose-dependently in the MD and HD groups (4, 5, 7, and 10 MDMs, MDFs, HDMs, and HDFs affected, respectively, compared to 0 controls). Drug-related ptosis primarily occurred during the first few days after treatment initiation and was no longer apparent thereafter. No other drug-related clinical signs were observed.

Body Weight and Food Consumption

During the treatment period, compared to controls, body weight and/or weight gain were decreased in MD and HD males and to a lesser extent in HD females (Figure 32), which correlated with decreased food consumption. At the end of the treatment period, cumulative weight gain was decreased by 7.7%, 9.5%, and 4.5% in MDMs, HDMs, and HDFs, respectively; and cumulative food consumption was decreased by 8.5%, 10.3%, and 6.4% in MDMs, HDMs, and HDFs, respectively. These decreases were reversible during the recovery period. Figure 32. Drug-related Decreases in Body Weight and/or Weight Gain in the Juvenile Rat Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 0, 43, 130, and 217 mg/kg/day Abbreviations: SPN = viloxazine

Ophthalmoscopy

There were no drug-related ophthalmic findings. Incidental findings of unilateral uveitis and retinal degeneration were observed at comparable incidences and/or severity across all groups, including the controls.

Hematology

Compared to the controls, there were no drug-related changes in hematology parameters.

Clinical Chemistry

Compared to the controls, there were no drug-related changes in clinical chemistry parameters. At the end of the treatment period, HDMs had a slightly increased globulin concentration (11%). Given the small magnitude and lack of correlative findings, this is considered to be incidental.

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Urinalysis

Compared to controls, there were no drug-related changes in urinalysis parameters. A few incidental changes occurred; however, they are not considered to be drug-related or adverse due to their small magnitude and/or lack of a clear dose relationship.

Sexual Maturation

There were no drug-related effects on sexual maturation. Despite the slightly lower body weight and/or weight gain in the MD and HD groups, the average days of sexual maturation (preputial separation and vaginal opening) were comparable across all groups.

Reproductive Capacity

Compared to the controls, there were no drug effects on reproductive capacity. Sperm parameters (count, density, motility, and morphology) and estrous cycling were not affected. The fertility indices were 94.4%, 80%, 94.1%, and 100% in the control, LD, MD, and HD groups, respectively. At the scheduled cesarean, compared to the controls, no drug-related changes were observed; the numbers of corpora lutea, implantation sites, viable and nonviable embryos, and pre- and post-implantation loss were comparable across all groups.

CNS/ Neurobehavioral Assessment

Motor Activity

At the end of the treatment or recovery period, compared to the controls, there were no significant drug effects on motor activity. A decrease in motor activity was initially observed in HDFs at about 2 hours postdose on PND 74 or 75 (~25%, relative to controls); however, a reassessment prior to dosing on the next day (PND 76 or 77) did not show any difference, suggesting the decreases in motor activity to be transient rather than a long-term effect.

Functional Observational Battery

Compared to controls, there were no drug-related effects on the functional observational battery (FOB) during the treatment (PND 33 and 76) or recovery (PND 90) period.

Acoustic Startle

Compared to controls, there were no drug-related effects on acoustic startle during the treatment (PND 72) or recovery (PND 92) period.

Learning and Memory (M-Watermaze Performance)

Compared to controls, there were no drug-related effects on learning and memory (M- Watermaze performance) during the treatment (PND 68) or recovery (PND 83) period.

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Bone Evaluation

At the end of the treatment period, compared to controls, there were no drug-related effects on femur length. However, femur weights were slightly reduced (~8%) in male rats at all doses without a clear dose relationship. Nevertheless, the decreases were reversible after recovery. Therefore, they are not considered to be adverse. Females were not affected.

Gross Pathology

At the end of the treatment or recovery period, compared to controls, there were no drug-related gross pathology findings.

Organ Weights

Compared to controls, there were no drug-related changes in organ weights. A few incidental changes in organ weights were noted; however, there was no clear dose relationship or correlative histopathology findings; therefore, they are not considered to be drug-related.

Histopathology

At the end of the treatment or recovery period, histopathology evaluation was performed in organ/tissues collected from control and HD animals and any gross lesions. Compared to the controls, there were no drug-related changes in histopathology.

Toxicokinetics

On PNDs 23 and 72 (days 1 and 50 of dosing), blood samples were collected from designated animals at 0.5, 1, 2, 4, 8, and 24 hours postdose.27 The TK parameters of viloxazine were analyzed. A single control sample on PND 72 had a low level of viloxazine (<3% of the Cmax in the LD group), which is most likely due to cross-contamination. Given the small value, it does not affect TK data interpretation. On both sampling days, after oral administration, viloxazine was absorbed relatively rapidly, with Tmax values of 0.5 to 4 hours and T1/2 values of 0.6 to 3.4 hours. In both sexes, the exposure (AUC) increased slightly greater than dose proportionally. On PND 23, the exposure levels were comparable between males and females, whereas on PND 72 the exposure levels were slightly higher in females than in males (female-to-male ratio, 1.46 to 2.32). Repeat administration led to slightly reduced exposure levels on PND 72 relative to PND 23 (Table 138).

27 Blood samples were collected from TK animals on PND 23 and from main-study animals on PND 72. Control samples were collected only at 0.5 hour postdose.

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Table 138. Summary Toxicokinetic Parameters of Viloxazine in the Juvenile Rat Study

Source: Excerpted from the Applicant’s study reports Doses are presented as viloxazine hydrochloride; the free base-equivalent doses are 0, 43, 130, and 217 mg/kg/day Abbreviations: AUC = area under the curve; T = time 13.2.8. Phototoxicity

In a spectral absorbance assay (Study 812-Tox2019-056), the maximal absorption for viloxazine was detected at 290 nm with a molar extinction coefficient of 56.62 L/mol*cm, which is below the threshold of 1000 L/mol*cm. Therefore, viloxazine is not considered to have significant phototoxicity potential. 14. Clinical Pharmacology Assessment: Additional Information 14.1. In Vitro Studies

Protein Binding (Study 809V-TOX2007-026)

Plasma protein binding was determined in plasma at concentrations of 0.5, 1, 3 and 10 µg/mL [14C]-viloxazine by ultrafiltration. The results demonstrate that [14C]SPN-809V was moderately bound to rat, dog and human plasma proteins (40.8% to 82.2%). In human, the mean plasma protein binding of [14C]-viloxazine ranged from 82.2% at 0.5 µg/mL to 75.7% at 10 µg/mL.

Blood to Plasma Ratio (Study 812V-TOX2018-030)

Pooled male human (n=3) whole blood was dosed with viloxazine at nominal concentrations of 0.745, 7.45 and 74.5 μg/mL and incubated at 37°C on a rotary mixer for 0, 60 and 120 minutes. After incubation, a packed cell volume (hematocrit) determination was made and duplicate aliquots of blood were analyzed by LC-MS/MS (viloxazine) or radioactivity ([3H]-chloroquine). The results indicated that viloxazine does not preferentially accumulate in human blood cells.

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Viloxazine is stable for up to 120 minutes in human blood at 37°C. The overall blood/plasma ratio for viloxazine at Cmax in human (7450 ng/mL) was 0.509.

Metabolism of [14C] Viloxazine (Report No. 809V-TOX2007-032)

The cytochrome P450 (CYP) isoenzymes involved in the metabolism of viloxazine were identified in human hepatic microsomes from human donors and recombinant (cDNA- expressing) human CYP Supersomes™. CYP450 isoenzymes were identified in inhibition studies with pooled human hepatic microsomes, CYP-specific inhibitory antibodies (or the CYP- selective chemical inhibitor sulfaphenazole for determination of CYP2C9 involvement), and microsomes containing individual cDNA-expressed human CYP isoenzymes. Incubation of [14C]viloxazine with pooled human liver microsomes in the presence of NADPH resulted in the formation of several metabolites. The metabolites that could be identified by liquid chromatography-tandem mass spectrometry (LC/MS/MS) consisted of hydroxylation and de-ethylation products of viloxazine. M8 (hydroxy-SPN-809V) was the major in vitro metabolite in pooled human liver microsomes. A Michaelis–Menten (MM) kinetic analysis of M8 formation yielded a Km of 35.2±9.4µM and a Vmax of 64.3±4.7 pmol/minute/mg microsomal protein. Incubations with inhibitors and with cDNA-expressed human CYP isoenzymes suggested that the major metabolite of [14C]viloxazine, M8, was formed primarily by CYP2D6. One other metabolite, MB (unidentified) was also formed primarily by CYP2D6. Four other metabolites, MA (unidentified), M6 (hydroxy-viloxazine), M11 (hydroxy-viloxazine), and MC (unidentified), were formed by multiple CYP isoenzymes, primarily CYP1A2, 2B6, 2D6, and 3A4.

Inhibition of CYP Isozymes by Viloxazine (Study 812V-TOX2018-024)

The potential of viloxazine to act as a reversible competitive inhibitor (0-minute preincubation with test compound) and as a time-dependent inhibitor (30-minute preincubation with test compound in the presence and absence of NADPH cofactor) was determined. Viloxazine (0, 3.37, 10.1, 33.7, 101, 303, and 1010μM and 0.001, 0.003, 0.1, 0.3, 1 and 10μM [with CYP1A2 only]) was incubated with pooled human liver microsomes, β-NADPH, phosphate buffer, and CYP-selective chemical substrates. Following incubation, the levels of known metabolites from each CYP-catalyzed reaction were quantified by LC-MS/MS. The results suggested that viloxazine did not inhibit CYP2C8, 2C9, or 2C19; the IC50 values for these enzymes were >1010μM. The data suggested that viloxazine acts as a reversible inhibitor of CYP1A2, 2B6, 2D6, and 3A4/5 with IC50 values of 0.269, 184, 141 and 221 (midazolam) and 352 (testosterone) μM, respectively. No time-dependent inhibition by viloxazine was observed, except for CYP1A2. Viloxazine was potentially a time-dependent inhibitor of CYP1A2, with an IC50 value of 0.0436μM (~0.01 μg/mL) following a 30-minute preincubation with cofactor (NADPH).

Induction Potential of CYP1A2, 2B6, and 3A4 by Viloxazine (Study 812V-TOX2017-002)

The potential for viloxazine to induce CYP1A2, 2B6 and 3A4 was evaluated using cryopreserved human hepatocytes. Viloxazine at 1.4, 3.5, 14, 35, 70, 140 and 350μM was used to assess the effects on CYP1A2, 2B6, and 3A4 mRNA levels. Following exposure, RNA was extracted from the cells and the mRNA levels of the target genes analyzed. In addition to viloxazine, cultured hepatocytes from the same three donors were exposed to the prototypical

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inducing compounds omeprazole (CYP1A2), phenobarbital (CYP2B6), and rifampicin (CYP3A4), as well as the noninducing agent flumazenil and appropriate solvent controls. The overall induction response was assessed using the calculated R value (R3), where an R3 value of <1/1.1 (i.e., 0.9) would be considered indicative of enzyme induction. The results indicated that there was no cytotoxic effect mediated by viloxazine at up to 140μM. R3 values were calculated using a worst-case scenario Cmax of 7450 ng/mL and were found to be 0.068 and 0.0442 for CYP1A2 (donor 1 and 2, respectively) and 0.161 for CYP2B6.Viloxazine is a potential inducer of CYP1A2 if the Cmax value is >38 ng/mL. Viloxazine is a potential inducer of CYP2B6 if the Cmax value is >108 ng/mL. In this study, the values for omeprazole- mediated CYP1A2 induction (AhR-mediated), phenobarbital-mediated CYP2B6 induction (CAR-mediated), and rifampicin-mediated CYP3A4 induction (PXR-mediated), were acceptable at the concentrations dosed, therefore, the controls were suitable. Another in vitro study (Supernus 809V-TOX2007-009, submitted under IND (b) (4) ) suggests that viloxazine at ≤0.2 μg/mL is not an inducer of cytochrome P450. At ≥2 μg/mL, viloxazine may be an inducer of CYP1A1/1A2 (based on one of three donors), and at ≥20 μg/mL, viloxazine may be an inducer of CYP2B6 and CYP2C9. Based on the population PK analysis, the average Cmax at steady state in adolescents with a daily dose of 600 mg is predicted to be approximately 6.5 μg/mL (refer to Section III.14.4). Therefore, viloxazine is considered a potential inducer of CYP1A2 but not of CYP2B6 in the clinical setting.

Evaluation of Drug Transporters Involved in the Disposition of Viloxazine

Viloxazine was evaluated as a potential substrate of OATP1B1*1a and OATP1B3. Viloxazine (at 0.659, 2.20, 6.59 and 19.8μM) was incubated with HEK293 cells singly transiently transfected with the transporters (Corning® Transporto Cells™). Incubations contained either viloxazine or the OATP1B probe substrate [3H]estradiol 17β-glucuronide ([3H]E17βGluc;2 μM) with and without the reference inhibitor cyclosporine A (10μM). Viloxazine was assessed with cyclosporine A at the lowest and highest test compound concentration only. [3H]E17βGluc was assessed with and without cyclosporine A at a single concentration to determine the extent of inhibition and to demonstrate a fully functioning assay system. Probe substrate concentrations were quantified by radioactivity measurement using liquid scintillation counting and viloxazine concentrations were measured by LC-MS/MS. There was no effect of cyclosporine A on the rate of uptake of viloxazine into transfected cells. The uptake ratio of viloxazine was <2 in all incubation conditions and so it is not considered an in vitro substrate for OATP1B1*1a. Cyclosporine A did not affect the viloxazine uptake ratio relative to the control at a viloxazine concentration of 19.8μM. The uptake ratio of viloxazine was <2 in all incubation conditions and it is not considered an in vitro substrate for OATP1B3. Viloxazine is not considered an in vitro substrate of the OATP1B1*1a or OATP1B3 transporters.

Viloxazine as an Inhibitor of Drug Transporters (Study 81V-TOX2018-026)

ABC transporters (P-gp and BCRP) inhibition by viloxazine was assessed in transfected MDCKII cells (PreadyPort™ Ready-to-use Transfected Monolayer (P-gp or BCRP)). Viloxazine was incubated with the cells in triplicate with a known P-gp or BCRP substrate in the presence of varying concentrations of test compound. At the end of an appropriate incubation period, the

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probe substrate concentrations in the samples (donor compartment sampled at 120 minutes; receiver compartment sampled at 60, 90, and 120 minutes) were quantified by radioactivity measurement using liquid scintillation counting. Viloxazine was also assessed as a potential inhibitor of the OATP1B1*1a, OATP1B3, MATE1, and MATE2-K SLC transporters. The potential of viloxazine to act as a direct inhibitor (0-minute preincubation in the absence of test compound) and as a time-dependent inhibitor (30-minute preincubation with test compound) was determined for OATP1B1*1a and OATP1B3. Incubations of viloxazine were conducted in the presence of probe substrates of the transporters. There was concentration-dependent inhibition of the net efflux ratio of the P-gp substrate (digoxin) and BCRP substrate (prazosin), resulting in IC50 values of 1.50 and 1.68mM, respectively. The Igut/IC50 value of viloxazine was calculated as 6.73 and 6.01 for P-gp and BCRP, respectively, based on a viloxazine maximum clinical dose of 600 mg. Therefore, viloxazine is not expected to be an inhibitor of Pgp or BCRP to cause clinically relevant drug interaction because the Igut/IC50 values were <10.

Viloxazine was a direct inhibitor of the OATP1B1*1a and OATP1B3 transporters, with IC50 values of 1.84 and 2.70mM respectively. Furthermore, viloxazine was a time-dependent inhibitor of these transporters, with IC50 values of 0.903 and 0.585mM, respectively, following 30-minute preincubation. The calculated R value was <1.1; therefore, viloxazine is not expected to undergo clinically important interactions with OATP1B1*1a and OATP1B3 substrates.

Viloxazine was a weak inhibitor of the MATE1 transporter, with a reported IC50 value of 140μM. The calculated Imax,u/IC50 ratio was 0.05. Therefore, a clinically important interaction is unlikely. MATE2-K was not inhibited by viloxazine (IC50 >330μM and Imax,u/IC50 ratio <0.02). Another transporter inhibition study (812V-TOX2012-005) determined whether viloxazine hydrochloride inhibits substrate transport by P-gp, BCRP, OAT1, OAT3, OCT2, OATP1B1, or OATP1B3. Viloxazine at 150μM did not inhibit the transport of probe substrate by OATP1B1, OATP1B3 or BCRP, but inhibited P-gp, OAT1-, OAT3-, and OCT2-mediated transport by 9.41%, 29.7%, 33.4%, and 43.9%, respectively. The tested concentration of viloxazine was about 50-fold the human unbound Cmax. Because the inhibition of transporter activities was <50% in the presence of 150μM viloxazine, the unbound Cmax/IC50 for viloxazine should be <0.1. Therefore, it is not expected to be clinically important. 14.2. Bioanalytical Analysis The validated bioanalytical method (TR-10-034.00) used to determine the concentrations of viloxazine and its metabolite (5-hydroxyviloxazine glucuronide) in human plasma in the pivotal clinical and pharmacokinetic studies consisted of liquid extraction plus liquid chromatography- tandem mass spectrometry (LC/MS/MS). The concentration range was 0.01 to 10 µg/mL. The- inter-run precision and intra-run precision were ≤10%. The accuracy was 97% to 107%. An incurred sample reanalysis was conducted and met the acceptance criteria. The quality control samples were adequate. A bioanalytical method (TR-18-019.00) was used to determine the concentration of 5-hydroxyviloxazine glucuronide. The concentration range was 0.005 to 10 µg/mL. The inter- and intra-run precisions were ≤14%. The accuracy was 94% to 115%. The viloxazine concentration in human urine was determined using an LC/MS/MS method. The concentration range in urine was 0.005 to 10 µg/mL. The inter- and intra-run precisions were

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≤8% and ≤7%, respectively. The accuracy was 88% to 114%. The 5-hydroxyviloxazine glucuronide concentration in human urine was measured by LC/MS/MS with a concentration range of 10 to 10,000 ng/mL. The inter- and intra-run precisions were ≤4.5% and ≤4.9%, respectively. The accuracy was 92% to 102.6%. An LC/MS/MS method was used to determine the concentration of methylphenidate in human plasma with a concentration range of 0.05 to 5.0 ng/mL. The inter- and intra-run precisions were ≤3% and the accuracy was 89% to 98%. An LC/MS/MS bioanalytical method was validated to determine the concentrations of d-amphetamine and l-amphetamine in human plasma over the range of 0.500 to 80.0 ng/mL for d-amphetamine and 0.200 to 32.0 ng/mL for l-amphetamine. The inter- and intra-run precisions were ≤2.9% and ≤3.0%, respectively. The accuracy was 96.2% to 110%. A bioanalytical method (ATM-2380) was validated to determine the concentration of moxifloxacin in human plasma over the range 25.0 to 5000 ng/mL. The inter- and intra-run precisions were ≤4.1% and ≤5.9%, respectively. The accuracy was 99.6% to 104.2%. A bioanalytical LC/MS/MS method was validated to determine the concentrations of dextromethorphan in human plasma over the range 0.0300 to 30.0ng/mL. The inter- and intra-run precisions for dextromethorphan were ≤5.4% and ≤6.4%, respectively. The accuracy was 98.3% to 105.9%. An LC/MS/MS bioanalytical method was validated to determine the concentrations of caffeine in human plasma over the range 50.0 to 15,000 ng/mL. The inter- and intra-run precisions were ≤3% and ≤3.2%. The accuracy was 99.2% to 105%. A validated LC/MS/MS bioanalytical method was used to determine the concentration of midazolam in human plasma over the range 0.200 to 40.0 ng/mL. The inter- and intra-run precisions were ≤3.8%. The accuracy was 97.8% to 102.7%. All acceptance criteria were met for assay methodologies and validation of viloxazine, 5-hydroxyviloxazine glucuronide, in plasma and urine. The acceptance criteria for caffeine, dextromethorphan, midazolam, d-amphetamine, methylphenidate, and moxifloxacin were met. The validation data demonstrated that the methods were precise, accurate, sensitive, specific, and reproducible. The validated assays are, therefore, acceptable. 14.3. In Vivo Studies 14.3.1. ADME Studies

Mass Balance Study

Study 812P111 was a single-center, open-label, nonrandomized, single-dose study in 7 healthy male subjects. Subjects received a single oral dose of [14C]-viloxazine solution (20 mL) containing 100 mg of viloxazine (as free base) and not more than (NMT) 8.7 MBq (236 μCi) [14C]-viloxazine. Blood, urine, and feces samples were taken for determination of the concentrations of viloxazine and its metabolites in each matrix by LC-MS/MS. Two major components (P1 and P2) accounted for ≥10% of the total sample radioactivity in plasma in at least one subject. P1 accounted for 10% to 16% of the total sample radioactivity in plasma. P1 was identified as 5-hydroxyviloxazine glucuronide. P2 accounted for 53% to 72% of the total sample radioactivity in plasma. P2 was identified as unchanged viloxazine. Plasma concentrations of total radioactivity were higher than those of total viloxazine, with geometric mean Cmax and AUC values approximately 1.5- and 2.0-fold greater, respectively.

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Two major components (U1 and U3) accounted for ≥10% of the total sample radioactivity in urine. A mean of 99.8% of the dose was excreted in the urine. U1 accounted for 22% to 33% of the total sample radioactivity. U1 was detected (>10% of sample radioactivity) in all of the 7 urine samples analyzed and was also detected in plasma (referred to as P1). U3 accounted for 17% to 28% of the total sample radioactivity in urine. U3 was identified as unchanged viloxazine (referred to as P2) and was detected (>10% of sample radioactivity) in all 7 of the urine samples analyzed. Following administration of a single oral dose of [14C]-viloxazine, a mean of 103.165% (range 101.72% to 104.29%) of the radioactivity administered was recovered by the end of the sampling period (96 hours postdose), with approximately 90% of the dose recovered within the first 24 hours of dosing. An average of 102.495% of the total radioactivity was recovered from urine and 0.670% from feces. Urinary excretion is the major route of elimination of viloxazine and its metabolites. Unchanged viloxazine and its 5-hydroxy glucuronide metabolite were the only moieties excreted in urine in amounts >10% of total radioactivity.

Bioavailability Study

Study 812P103 was a single-center, open-label, randomized, 2-period, 2-sequence, crossover study in healthy adult subjects that evaluated the steady-state PK and relative bioavailability under fasted conditions. Subjects received a single dose of the assigned medication (SPN-812 ER or SPN-812 IR) on the morning of the first dosing day. PK blood samples were collected over the next 48 hours. On days 3 to 6, Treatment A (200 mg SPN-812 ER) was administered once daily and Treatment B (66.7 mg SPN-812 IR) thrice daily starting in the morning. PK blood sampling continued up to 24 hours after the morning dose on day 6. Predose PK blood samples were collected on days 4 and 5. Subjects were re-entered after an 8-day washout period and ≥10 hours prior to the first dose of period 2. The dosing schedule and study procedures were as for period 1. A validated LC/MS/MS analytical method was used to determine viloxazine (SPN-812) concentrations (calibration range 0.01 to 10.0 µg/mL). The PK parameters after administration of single and multiple doses of SPN-812 (viloxazine) are provided in Table 139, Table 140, and Table 141. Table 139. SPN-812 (Viloxazine) Pharmacokinetic Parameters after a Single Dose on Day 1, Mean ± SD (%CV) Parameter N Treatment A (SPN-812 ER) Treatment B (SPN-812 IR) Cmax (µg/mL) 28 1.33±0.335 (25.2) 3.42±0.802 (23.4) a Tmax (hours) 28 5 (3.00, 9.00) 1.75 (0.50, 6.00) AUC(0-t) (h*µg/mL) 28 26.0±9.94 (38.2) 30.9±9.87 (31.9) AUC(0-inf) (h*µg/mL) 28 27.3±12.2 (44.8) [N=27] 31.2±9.88 (31.6) T½ (hours) 28 7.02±4.74 (67.5) [N=27] 4.26±1.30 (30.4) Source: Applicant’s study 812P103, page 45 a Tmax = Median (range) Abbreviations: AUC = area under the curve; ER = extended release; IR = immediate release; SPN = viloxazine

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Table 140. SPN-812 (Viloxazine) Steady-State Pharmacokinetic Parameters on Day 6 after Multiple Doses, Mean ± SD SPN-812 ER (qd) SPN-812 IR (q8h) (N=28) (N=27) Parameter 0-24 h 0-24 h 0-8 h Cmax,ss (µg/mL) 1.66±0.503 (30.4) 1.92±0.496 (25.8) 1.89±0.506 (26.7) a Tmax,ss (hours) 5.0 (2.0, 9.0) 1.5 (0.50, 10.0) 1.0 (0.50, 3.00) Cmin,ss (µg/mL) 0.388±0.230 (59.3) 0.611±0.289 (48.9) 0.738±0.346 (46.9) Cavg (µg/mL) 1.03±0.355 (34.5) 1.14±0.359 (31.6) 1.25±0.392 (31.3) AUC(0-24h) (h*µg/mL) 24.7±8.52 (34.5) 27.3±8.62 (31.6) 9.90±3.10 (31.3) %FL (%) 128±27.8 (21.7) 121±32.8 (27.1) 97.3±29.9 (30.7) a Source: Applicant’s study 812P103, page 46 Tmax = Median (range) Abbreviations: AUC = area under the curve; ER = extended release; IR = immediate release; SPN = viloxazine Table 141. Viloxazine Steady-State Relative Bioavailability Following Administration of SPN-812 ER vs. IR Geometric LS Mean LS Mean Ratio (Test/Ref) PK Parameter SPN-812 ER (Test) SPN-812 IR (Ref) Estimate (%) CV (%) 90% CI Cmax,ss (µg/mL) 1.593 1.844 86.4 15.7 (80.3, 92.9) Cavg (µg/mL) 0.981 1.071 91.6 12.5 (86.4, 91.1) AUC(0-24) (h*µg/mL) 23.5 25.7 91.6 12.5 (86.4, 97.1) Cmin (µg/mL) 0.320 0.534 60.0 41.3 (49.9, 72.1) %FL (%) 124.9 119.0 105.0 16.4 (97.3, 113.2) Source: Applicant’s study 812P103, page 48 Abbreviations: AUC = area under the curve; CV = covariance; ER = extended release; FL = peak-to-trough fluctuation; IR = immediate release; LS = least squares; PK = pharmacokinetic; SPN = viloxazine Following a single-dose administration, the PK profiles of once-daily (1×200 mg) SPN-812 ER showed similar exposures (AUCs) but lower Cmax values compared to SPN-812 IR. The Tmax and T1/2 values of viloxazine (SPN-812 ER capsules) were about 5 and 7 hours, respectively. There was no significant difference in systemic exposure to viloxazine after multiple-dose administration of the ER and IR SPN-812 formulations for 6 days. Steady state was reached after 2 days of daily dosing of SPN-812 ER. The peak-to-trough fluctuation, % FL, was about 128% for SPN-812 ER.

Food Effect

Study 812P105 was a single-center, randomized, open-label, single-dose, 3-period, 3-treatment, 3-sequence crossover in study in 27 healthy adult subjects. For Treatment A, subjects swallowed an intact 200 mg viloxazine capsule after 10 hours overnight fast. For Treatment B, subjects consumed the contents of a 200 mg viloxazine capsule sprinkled on applesauce. For Treatment C, subjects swallowed an intact 200 mg viloxazine capsule after a high-fat (50% total caloric content), high-calorie (800 to 1000 calories) meal. The washout period between drug administrations was 4 days. Plasma PK samples were collected up to 48 hours. A validated LC/MS/MS method was used to determine viloxazine concentrations (calibration range 0.01 to 10 µg/mL).

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Table 142. Effect of Food on Viloxazine (SPN-812) B vs. A (Sprinkled vs. Intact) Geometric Meana Ratio (%)b 90% CI PK Parameter B A B/A Lower Upper Cmax 1.21 1.34 90.10 83.35 97.40 AUClast 23.00 24.54 93.71 89.09 98.57 AUCinf 24.45 25.64 95.37 89.80 101.28 C vs. A (Fed vs Fasted) C A C/A Lower Upper Cmax 1.22 1.34 90.86 84.05 98.21 AUClast 22.01 24.54 89.68 85.26 94.33 AUCinf 23.68 25.64 92.35 86.96 98.07 Source: Applicant’s study 812P105, pages 44–45a Geometric means for intact 200 mg SPN-812 ER capsule–fasted (A); sprinkled 200 mg ER capsule–fasted (B); and 200 mg SPN-812 ER capsule–fed (C) based on the least squares mean of log-transformed parameter values b Ratio (%)=geometric mean (GM) B/GM A or GM C/GM A Abbreviations: AUC = area under the curve; ER = extended release SPN = viloxazine

Sprinkling of the contents of viloxazine on applesauce decreased the Cmax and total exposure (AUClast and AUCinf) by about 10%, and 5% to 6%, respectively. Administration of viloxazine capsule after a high-fat meal (800 to 1000 kcal) reduced the Cmax and total exposure by about 9% and 8% to 10%, respectively. These differences are not expected to be clinically meaningful. The Tmax values after administration of viloxazine sprinkled on applesauce, and in an intact capsule under fed and fasted conditions, were 5, 7, and 5 hours, respectively. Therefore, viloxazine can be taken with or without food and can be administered sprinkled on applesauce. 14.3.2. Drug-Drug Interactions

Effect of Viloxazine on the Pharmacokinetics of Other Drugs

Effect of Viloxazine on Select CYP Substrates

Study 812P113.1 evaluated the effect of multiple-dose viloxazine ER on the PK of CYP1A2, CYP2D6, and CYP3A4 substrates given as a single dose to healthy adults under fasting conditions in an open-label, 3-period, 3-treatment, 1-sequence crossover study (Figure 33). Figure 33. Drug-Drug Interaction Study Schematic

Source: Applicant’s study 812P113.1, page 39 Abbreviations: ER = extended release; PK = pharmacokinetic; SPN = viloxazine

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MCC contained a caffeine 200 mg tablet, dextromethorphan 30 mg capsule, and midazolam 0.025 mg/kg syrup. The viloxazine ER dose was 900 mg QD. PK blood draws were performed over a 48-hour period. Table 143. Statistical Analysis of Caffeine and Its Metabolite (Paraxanthine) Pharmacokinetic Parameters Following Administration of MCC Alone and Coadministration with Viloxazine ER

Source: Applicant’s study 812P113.1, page 73 Abbreviations: AUC = area under the curve; ER = extended release; SPN = viloxazine Table 144. Statistical Analysis of Dextromethorphan and Its Metabolite (Dextrorphan) Pharmacokinetic Parameters Following Administration of MCC Alone and Coadministration with Viloxazine ER

Source: Study 812P113.1, page 79 Abbreviations: AUC = area under the curve; ER = extended release; SPN = viloxazine

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Table 145. Statistical Analysis of Midazolam and Its Metabolite (1-Hydroxymidazolam) Pharmacokinetic Parameters Following Administration of MCC Alone and Coadministration with Viloxazine ER

Source: Study 812P113.1, page 85 Coadministration of viloxazine ER with midazolam increased the midazolam AUC about 1.7-fold but did not affect the Cmax. therefore, viloxazine is a weak inhibitor of CYP3A4. Abbreviations: AUC = area under the curve; ER = extended release; SPN = viloxazine

Effect of Viloxazine on Stimulants (d-Amphetamine and Methylphenidate)

Study 812P113.2 evaluated the interaction of lisdexamphetamine (Vyvanse®) coadministered with viloxazine ER. The study was a randomized, single-dose, 3-period, 3-treatment, 6-sequence crossover study in healthy adults. Subjects were administered their treatment after an at least 10-hour overnight fast according to a randomized schedule. There was a 4-day washout period between treatments. Blood samples for PK analysis were collected over a 96-hour period. Treatment A: Vyvanse 50 (1×50) mg capsule, single dose (n=35) Treatment B: Viloxazine ER 700 (3×200+1×100) mg capsules, single dose (n=34) Treatment C: Viloxazine ER 700 mg+Vyvanse 50 mg capsules, single dose (n=34)

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Table 146. Statistical Analysis of d-Amphetamine Pharmacokinetic Parameters Following Administration of Vyvanse Alone (Treatment A) and Coadministration with Viloxazine ER (Treatment C)

Source: Applicant’s study 812P113.2, page 58d-amphetamine is the active moiety in lisdexamphetamine (Vyvanse) Source: Applicant’s study 812P113.2, page 58Abbreviations: AUC = area under the curve; ER = extended release Abbreviations: AUC = area under the curve; ER = extended release Study 812P113.3 evaluated the interaction of 36 mg methylphenidate (Concerta®) coadministered with 700 mg of viloxazine ER. The study was a randomized, open-label, single- dose, 3-period, 3-treatment, 6-sequence crossover study in healthy adults. The treatments were administered after an overnight fast of at least 10 hours. There was a washout period of 4 days between treatments. Blood samples for PK analysis were collected over a 96-hour period. Treatment A: Concerta 36 (1×36) mg single-dose oral tablet (n=34) Treatment B: Viloxazine ER 700 (3×200 + 1×100) mg single-dose oral capsules (n=34) Treatment C: Concerta 36 mg+viloxazine ER 700 mg (n=34) Table 147. Statistical Analysis of Methylphenidate Pharmacokinetic Parameters Following Administration of Concerta Alone (Treatment A) and Coadministration with Viloxazine ER (Treatment C)

Source: Applicant’s study 812P113.3, page 59 Abbreviations: AUC = area under the curve; ER = extended release There was no significant effect of viloxazine of the PK of d-amphetamine, the active moiety in lisdexapmhetamine, after single-dose coadministration of Vyvanse and viloxazine ER. There was no significant effect of viloxazine on the PK of methylphenidate after single-dose coadministration of Concerta and viloxazine ER.

Effects of Other Drugs on Viloxazine

Studies 812P113.2 and 812P113.3 evaluated the effects of d-amphetamine and methylphenidate on the PK of viloxazine following their coadministration (Table 148 and Table 149).

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Table 151. Summary of Viloxazine Pharmacokinetics After Single-Dose Administration to Subjects with Mild, Moderate, and Severe Renal Impairment and Matched Normal-Renal-Function Controls

Source: Applicant’s study 812P112.1, page 101 Abbreviations: AUC = area under the curve; CL = clearance Mild or moderate renal impairment does not have a clinically significant effect on the PK of viloxazine. However, severe renal impairment increased the viloxazine AUC about 2-fold. Dose adjustment is recommended for patients with severe renal impairment.

Hepatic Impairment

Hepatic impairment studies were not conducted for this application. Viloxazine ER should not be used in this patient population. A postmarketing requirement (PMR) would be issued as part of the action items.

CYP2D6 Phenotypes

Study 812P113.1 evaluated the effect of CYP2D6 phenotype on the PK of viloxazine. The design was an open-label, 3-period, 3-treatment, 1-sequence crossover study in healthy adults to assess the PK of multiple doses of viloxazine ER in CYP2D6 poor metabolizers (PMs) and extensive metabolizers (EMs). Subjects were administered 900 mg of viloxazine ER once daily. The PK of viloxazine at steady state in PMs compared to EMs are listed in Table 152.

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Table 152. Summary of Viloxazine PK in CYP2D6 Poor Metabolizers and Extensive Metabolizers Following Multiple, Once-Daily Doses of 900 mg Viloxazine ER

Source: Applicant’s study 812P133.1, page 89 Abbreviations: AUC = area under the curve; ER = extended release; EM = extensive metabolizers; PM = poor metabolizers

The Cmax, Cmin, and AUC at steady state were about 21% to 33% higher in PM compared to EM subjects. This is not expected to be clinically meaningful. The median Tmax was about 5 hours for both PM and EM subjects. 14.4. Pharmacometrics Review 14.4.1. Executive Summary The Applicant’s population pharmacokinetic (PPK) analysis which supports labeling statements is reviewed. Few changes to Section 12 of the proposed label are suggested. Supportive information is provided for the proposed changes. 14.4.2. Applicant’s Analysis Objectives: (i) To simultaneously characterize the PPK of viloxazine and its metabolite 5-hydroxy-viloxazine glucuronide; and (ii) to test for covariate effects to identify potential sources of variability. Data: The PK data of 495 subjects from 4 studies (812P301, 812P302, 812P303, and 812P304) were used to develop PPK models for viloxazine. Method: Nonlinear mixed effect PK modeling was conducted using NONMEM software and the FOCE-I method. The base structural PK model was first developed to describe the PK profiles of viloxazine and its metabolite. Covariate modeling was conducted using forward addition (p<0.01 for 1 degree of freedom) and backward elimination (p<0.001 for 1 degree of freedom). Covariates including age, BMI, weight, height, gender, race, ethnicity, ALT, AST, and creatinine were tested. Alternative models were compared using the log-likelihood ratio test for nested models or the Akaike information criterion for non-nested models. The final model was evaluated using goodness-of-fit plots, visual predictive checks, and bootstrapping. Results: The PK of viloxazine was described by a one-compartment model with first-order absorption and elimination of the parent drug, and first-order metabolite formation and elimination (Figure 34). Body weight was added on volume of distribution of viloxazine and its metabolite, its metabolite clearance, viloxazine metabolic clearance. The parameter estimates of the final PPK model for viloxazine are shown in Table 153.

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Figure 34. Schematic Representation of the PK Model of Viloxazine

Source: Supernus population PK report: Figure 3, page 25 Abbreviations: ER = extended release; PK = pharmacokinetic; SPN = viloxazine Table 153. Parameter Estimates of the Applicant’s Final PPK Model

Source: Supernus PPK report: Table 9, page 34 Abbreviations: CLL = VLX clearance; CLM = serotonin-VLX-glucose clearance; CLV = metabolic clearance; CV = covariance; k12 = VLX absorption rate constant; PPK = population pharmacokinetic; V2/F = apparent volume of distribution for VLX; VLX = viloxazine The PPK model for viloxazine and its metabolite was assessed with diagnostics plots including goodness-of-fit (Figure 35) and visual predictive checks. Overall, goodness-of-fit plots adequately describe the PK data of viloxazine and its metabolite. The final pop PK model was

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used to simulate steady-state PK profiles of viloxazine, and NCA analysis was then performed to evaluate the impact of body weight on viloxazine exposure. 14.4.3. Reviewer’s Analysis

Evaluation of the Applicant’s PPK Model

The reviewer was able to run the Applicant’s final PPK model and obtained similar results. Model diagnostics for viloxazine are shown in Figure 35. The effect of the covariates on the PK of viloxazine was evaluated based on the PPK modeling results and the observed data. The impact of covariates was evaluated using PK data of viloxazine 400 mg for the following reasons: (i) Linear PK from 300 to 2100 mg/day, (ii) viloxazine 400 mg is a recommended dose for both age groups (children and adolescent), and (iii) adequate PK data for viloxazine 400 mg in both age groups with rich PK sampling (up to 6 hours postdose). Figure 35. Goodness-of-Fit Plots of the Applicant’s PPK Model for Viloxazine

Abbreviations: PPK = population pharmacokinetic

Effect of Body Weight

The PK data of 130 subjects dosed with viloxazine 400 mg were distributed into quartiles (i.e., first quartile: n=36, 21 to 45; second quartile: n=31, 45 to 53; third quartile: n=33, 53 to 63; and

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fourth quartile: n=30, 63 to 92.5) based on their weight distribution and plotted together with the corresponding median population predictions (Figure 36). Overall, the AUC and Cmax of viloxazine decreased with increasing body weight. Figure 36. Body Weight PK Data of Subjects Dosed with 400 mg Viloxazine

Top row, Individual PK profiles of viloxazine by body-weight quartile; black dashed line indicates median population predictions from the Applicant’s final PPK model. Bottom row, mean (95% CI) PK profiles of viloxazine by body-weight quartile. Red, green, cyan, and purple—first, second, third, and fourth quartiles of body weight, respectively. Abbreviations: PK = pharmacokinetic; PPK = population pharmacokinetic The effect of body weight on viloxazine and its major metabolite exposure was quantified by the Applicant by conducting PK simulations. The PK data of 263 children (median body weight 31.5 kg) and 199 adolescents (median body weight 57.25 kg) dosed with 100 to 600 mg were simulated and the resulting PK parameters were compared (Table 154). The estimated steady- state Cmax and AUC0-24 of viloxazine and its major metabolite at doses of 100 to 600 mg were approximately 40% to 50% higher in children compared to adolescents. However, the ADHD- RS-5 total scores of children and adolescents were similar (Refer to the Medical Officer’s review).

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Table 154. Estimated Viloxazine and Metabolite PK Parameters (Cmax and AUC0-24) at Steady-State in Children and Adolescents at Doses of 100, 200, 400, and 600 mg Cmax (µg/mL) AUC0-24 (µg*h/mL) Children of Adolescent of Children of Adolescent of Dose 31.5 kg 57.3 kg Change (%) 31.5 kg 57.3 kg Change (%) Viloxazine 100 1.6 1.f16 38 19.29 14.5 33 200 4.04 2.89 40 71.45 52.41 36 400 8.15 5.77 41 143.61 105.51 36 600 8.89 6.49 37 106.96 79.97 34 Viloxazine metabolite: 5-hydroxy-viloxazine glucuronide 100 1.04 0.74 41 13.17 9.24 43 200 2.66 1.79 49 47.8 32.36 48 400 5.17 3.49 48 93.72 63.94 47 600 5.2 3.56 46 70.14 48.94 43 Source: Adapted from the Supernus population PK report: Tables 13–20, pages 43–50 Abbreviations: AUC = area under the curve; PK = pharmacokinetic

Sex Effect

The PK data of 91 males and 39 females dosed with viloxazine 400 mg were plotted with the corresponding population predictions (Figure 37). The overlapping 95% CIs of the PK profiles by sex suggest a lack of a clinically relevant influence of sex on the PK of viloxazine.

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Figure 37. PK Data of Subjects Dosed with 400 mg Viloxazine by Sex

Top row, individual PK profiles of viloxazine by sex; black dashed line indicates median population predictions from the Applicant’s final PK model. Bottom row, mean (95% CI) PK profiles of viloxazine by sex. Red indicates male and cyan, female subjects. Abbreviations: PK = pharmacokinetic

Race Effect

The PK data of 48 black, 76 white, and 6 other subjects dosed with viloxazine were plotted with the corresponding median population predictions (Figure 38). The data for ‘other’ were sparse, resulting in wider confidence intervals. Overall, the overlapping 95% CIs of the PK profiles by race suggest a lack of a clinically relevant influence of race on the PK of viloxazine. The population PK model developed from a larger dataset (white [n=258], black [n=214], and other [n=23]) confirmed the above findings.

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Figure 38. PK Data of Subjects Dosed with Viloxazine by Race

Top row, individual PK profiles of viloxazine by race. Black dashed line indicates the median population predictions from the Applicant’s final PK model; Bottom row, mean (95%CI) PK profiles of viloxazine by race. Red, green, and blue indicate white, black, and other, respectively. Error bars for others are not shown due to the small sample size. Abbreviations: PK = pharmacokinetic 15. Trial Design: Additional Information and Assessment

This section describes the study design of the four phase 3 placebo-controlled studies (812P301, 812P302, 812P303, 812P304) that were submitted as evidence of safety and efficacy. These four studies have many design elements in common, so Study 312P301 is described in detail and then notable differences in the other studies are highlighted. In addition, this section briefly describes Study 812P202, a phase 2 dose-ranging study, and Study 812P310, a phase 3, open-label, long- term safety study.

812P301

Overview and Objective

The primary objective of the study was to evaluate the efficacy of viloxazine ER compared to placebo as monotherapy for ADHD in children ages 6 to 11 years.

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Study Design

812P301 was a multicenter, randomized, double-blind, three-arm, placebo-controlled study to evaluate the safety and efficacy of viloxazine ER (SPN-812) 100 mg and 200 mg in children with ADHD. The study was conducted entirely in the United States and included 34 research centers that spanned all geographic regions of the country. Patients ages 6 to 11 years weighing at least 20 kg with a diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM 5), confirmed with the Mini International Neuropsychiatric Interview for Children and Adolescents, were eligible to enroll. In addition, a baseline ADHD-RS-5 score of at least 28 and a baseline Clinical Global Impression- Severity (CGI-S) score of at least 4 were required. The ADHD-RS-5 is a validated rating scale that assesses symptoms that correspond to the DSM 5 criteria for ADHD. The scale consists of 18 questions, divided into hyperactivity/impulsivity and inattention subscales. Each question assesses the frequency of a symptom on a 4-point Likert scale. Raw scores are converted to percentile scores based on age and gender. The CGI-S is a clinician-completed, single-item assessment of the severity of a patient’s symptoms. Possible responses on the CGI-S are: 1=Not at all ill; 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; and 7=extremely ill. Patients entering the study must have been free of medication for ADHD for at least 1 week prior to randomization and be considered medically healthy by the Investigator (as assessed by physical examination, medical history, clinical laboratory tests, vital signs, and ECG). Female patients of childbearing potential had to be either abstinent or had to agree to use effective methods of birth control throughout the study. The exclusion criteria were:  Current diagnosis of a major psychological disorder. Patients with major depressive disorder were allowed in the study if free of episodes currently and for the last 6 months.  Current diagnosis of a major neurological disorder. Patients with seizures or a history of seizure disorder within the immediate family (siblings, parents), or a history of seizure-like events were excluded.  Current diagnosis of significant systemic disease.  Evidence of suicidality (defined as either active suicidal plan/intent or active suicidal thoughts or more than one lifetime suicide attempt) within 6 months of or at screening.  A BMI greater than the 95th percentile for age and gender.  History of an allergic reaction to viloxazine or related drugs.  Any food allergy, intolerance, restriction, or special diet that, in the opinion of the Investigator, could contraindicate the subject’s participation in this study.  Subjects who received any investigational drug within the longer of 30 days or 5 half- lives prior to day-1 dosing of the study medication.  Any reason, which, in the opinion of the Investigator, would prevent the subject from participating in the study.

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 Positive drug screen at the screening visit. A positive test for was allowed for subjects receiving a stimulant ADHD medication at screening; the subject was required to discontinue the stimulant at least 1 week prior to the baseline visit.  Pregnancy, breastfeeding, or refusal to practice abstinence or acceptable birth control during the study (for female patients of childbearing potential). Treatment assignment was conducted via an interactive web response system (IWRS), using a randomization schedule to determine the kit assignment for each patient being randomized. Patients, investigators, study site personnel, the Applicant, and the Contract Research Organization (CRO) clinical staff were blinded to the treatment assignments. The personnel who conducted the PPK analysis had access to data on plasma drug levels but were not otherwise associated with the conduct of the study and did not communicate with clinical site personnel about treatment assignments. The randomization schedule was filed securely by the IWRS vendor. Viloxazine ER and placebo were provided as capsules that were identical in appearance and were packaged in identical blister packs. Compliance with treatment was tracked using accountability logs. Criteria for withdrawal included withdrawal of consent, noncompliance, occurrence of unmanageable adverse events, loss to follow-up, or other personal reasons. No dietary restrictions were required. As noted above, any medications for ADHD must have been discontinued at least 1 week prior to randomization. Additional concomitant medications were prohibited during the study except nutritional supplements, numbing cream for venipuncture, and common over-the-counter remedies (e.g., acetaminophen and ibuprofen). Known CYP1A2 substrates were specifically prohibited. The investigational study drug (viloxazine ER or placebo) was administered once daily as intact placebo capsules, intact viloxazine ER 100 mg capsules, or as capsule content sprinkled on soft food. Treatment could be administered with or without food. The study protocol, protocol amendments, and the Informed Consent Form (ICF) were reviewed and approved by an Institutional Review Board (IRB). The CRO ( (b) (4) ) was involved in system set-up, monitoring, pharmacovigilance, data entry, data management, data security, statistical analysis, and medical writing. Patients were randomly assigned in a 1:1:1 ratio to receive either placebo, viloxazine ER 100 mg, or viloxazine ER 200 mg. The selected doses were based on the results of a phase 2 dose-ranging study (812P202), from which the Applicant concluded that the 100 mg and 200 mg doses were well tolerated in this age group. After a 4-week screening period, patients entered a 1-week dose titration phase and then a 5-week maintenance phase (Figure 39).

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The other secondary endpoints were:  The 50% responder rate, defined as the proportion of patients with a ≥50% reduction in the ADHD-RS-5 total score at EOS  CFB in the Parenting Stress Index (PSI-4) SF total score at EOS  CFB in the ADHD-RS-5 Inattention subscale score at EOS and Hyperactivity/Impulsivity subscale score at EOS  CFB in the Conners 3-Self Composite T-score at EOS (ages 8 to 11 years only)  Categorical CGI-I defined as the proportion of patients with a score of 1 (“very much improved”) or 2 (“much improved”) by visit The exploratory endpoints were:  CFB in the Conners 3-Parent T-score at EOS by individual domain  CFB in the Conners 3-Self T-score at EOS by individual domain  CFB in the WFIRS-P average score at EOS by individual subdomain  CFB in the Parenting Stress Index, Fourth Edition score at EOS by individual domain  PK of viloxazine and its metabolite, 5-hydroxy-viloxazine glucuronide  of viloxazine ER The safety endpoints were:  Adverse events  Clinical laboratory tests  Vital signs  Physical examinations  ECGs  Columbia Suicide Severity Rating Scale (C-SSRS) Table 155 (provided by the Applicant) summarizes the schedule of assessment activities in the study. Physical examinations, ECGs, and laboratory assessments were conducted at screening and at EOS. Vital sign monitoring, adverse event tracking, and monitoring for suicidal ideation and behavior (using the C-SSRS) were performed at every visit.

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Table 155. Schedule of Assessments (Study 812P301)

Source: Applicant’s Clinical Study Report, Time and Events Schedule, pages 35–36 a To be obtained prior to performing any study procedures. b Includes height and weight, excludes genitourinary system c Changes from screening only d Seated (5 minutes) heart rate and blood pressure, temperature, and respiratory rate e Self-report, only patients ages 8 to 11 years f At baseline, AEs were recorded only after SM was administered. Subjects with SAEs at EOS were followed until the event resolved or considered stable. g Titration began after the first dose of SM was administered h Optional PK substudy was performed between visits 3 and 8, inclusive. Samples were taken predose and postdose at hours 1, 2, 4, and 6. i EOS or last visit in the case of early discontinuation j Including any medical occurrences in the period from screening to first SM intake Abbreviations: ADHD-RS-5 = Attention Deficit Hyperactivity Disorder Rating Scale-5; CGI-I = Clinical Global Impression- Improvement; CGI-S = Clinical Global Impression-Severity of Illness; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; FOCP = female of childbearing potential; Mini-KID = Mini International Neuropsychiatric Interview for Children and Adolescents; PK = pharmacokinetics; PSI-4-SF = Parenting Stress Index, Fourth Edition, Short Form; WFIRS-P = Weiss Functional Impairment Rating Scale-Parent Report

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Patients were considered study completers if they completed all study visits up to and including visit 8 (EOS). The Applicant defined four patient populations for analysis purposes:  Randomized population: All enrolled patients that had a baseline visit scheduled and were randomized via the IWRS.  Safety population: All patients randomized into the study, who received at least one dose of study drug. Patients were analyzed according to the treatment they actually received.  Intent-to-treat (ITT) population: All patients who received at least one dose of study drug and had a baseline and at least one postrandomization ADHD-RS-5 assessment. Patients were analyzed according to the treatment to which they had been randomized.  Per-protocol population: All patients in the ITT population who had completed all 8 visits with no missing ADHD-RS-5 assessments and no major protocol violations. Patients were analyzed according to the treatment they received.

812P302

The primary objective of Study 812P302 was to evaluate the efficacy of viloxazine ER 200 mg and 400 mg compared to placebo as monotherapy for ADHD in adolescents ages 12 to 17 years. The design of this study was identical to that of Study 812P301 except for the age range, weight requirement (minimum weight for enrollment was 35 kg), and doses. The primary and secondary endpoints were also identical, except that the age-appropriate Stress Index for Parents of Adolescents was substituted for the Parenting Stress Index (PSI). This study was conducted at 33 research centers in the United States.

812P303

Study 812P303 evaluated the viloxazine ER 200 mg and 400 mg doses in children ages 6 to 11 years. The design of this study was also nearly identical to Study 812P301, except for the higher dose range and a longer (3 weeks) titration period (Figure 40). Patients were considered study completers if they attended all visits up to and including visit 10. This study was conducted at 28 research centers in the United States.

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Overall Assessment of Phase 3 Study Designs

Overall, these phase 3 studies were appropriately designed to meet their stated objectives. The design was typical of studies used to evaluate the safety and efficacy of psychiatric drugs and did not include any novel elements. The Applicant and the Agency reached agreement on the primary endpoint prior to submission of the NDA. However, the Agency did not agree with the use of the CGI-I as a key secondary endpoint because of its vulnerability to recall bias. The inclusion and exclusion criteria were appropriate to select a representative patient population and to mitigate the potential risks to patients in the studies. ADHD diagnosis in clinical practice is based on application of the DSM-5 criteria, which were also used in the phase 3 studies. The study excluded patients with a known history of seizure disorder or at high risk of seizures given that the risk of seizures in humans was unknown (convulsions occurred in multiple species in nonclinical studies). The protocol required reporting of seizures and seizure-like events as adverse events of special interest. The protocol also included appropriate prospective monitoring for potential safety signals of interest in this population, including cardiovascular adverse events, negative impacts on growth, and suicidal ideation.

812P202

Study 812P202 was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study that evaluated the efficacy and safety of viloxazine ER in pediatric patients ages 6 to 12 years. The study was conducted at 32 centers in the United States. The primary objective was to assess the effectiveness of viloxazine ER in reducing the symptoms of ADHD as measured by the ADHD Rating Scale–IV (ADHD-RS-IV). The secondary objectives were to assess the safety and tolerability in this patient population, effects on the CGI-I and CGI-S, effects on the hyperactivity/impulsivity and inattentive subscales of the ADHD-RS-IV, and to perform a responder analysis based on the ADHD-RS-IV total score. The study randomized patients (1:2:2:2:2) to receive placebo or viloxazine ER 100, 200, 300, or 400 mg once daily. The study included a 3-week titration phase and a 5-week maintenance phase (Figure 42). The inclusion criteria were: age 6 to 12 years, ADHD-RS-IV total score of ≥26, CGI-S of ≥4, and weight ≥20 kg. Patients must have stopped any ADHD medications at least 1 week before participation. The exclusion criteria were a history of major depressive disorder, obsessive compulsive disorder, posttraumatic stress disorder, or other anxiety disorder; significant physical illness; active suicidal ideation or >1 suicide attempt within the last 6 months; BMI ≥95%; substance or alcohol use within the last 3 months or positive toxicology screen; and pregnancy. The primary endpoint was the CFB to EOS in the ADHD-RS-IV total score. The schedule of assessments was similar to those in the phase 3 studies.

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Overall Assessment of Open-Label Safety Extension Study

Study 812P310 lacked a placebo arm and was not designed to determine whether observed adverse events or other clinical findings were likely associated with viloxazine ER exposure. However, changes from baseline in growth parameters, vital signs, and laboratory assessments were examined for long-term trends. In addition, the adverse event data were examined for any unexpected safety signals emerging with long-term use. 16. Efficacy Assessment Additional Information and Assessment 16.1. Gender, Race, Age This reviewer conducted an exploratory subgroup analysis by race, gender, and age. The primary efficacy analysis model, mixed model repeated measures (MMRM), was used to investigate the treatment effect. The subgroup analyses were post hoc and any findings could be due to chance. Study 301: Whites had a numerically better treatment effect than non-whites for both doses of SPN-812 ER compared to placebo; there were no substantial differences between males and females. Subjects ages 10 to 11 years, who were markedly fewer in number, had a numerically slightly smaller treatment effect. Study 302: Whites and males had a numerically better treatment effect than non-whites and females, respectively, for both doses of SPN-812 ER compared to placebo. This may have been due to the smaller sample size. Subjects ages 12 to 14 years versus those 15 to 17 years had a numerically greater treatment effect. Study 303: In general, there were no substantial differences among the subgroups. However, for the highest dose (SPN-812 ER 400 mg/day) the treatment effect in those ages 10 to 11 years was approximately half that in patients ages 6 to 9 years. Study 304: Non-whites (about half the sample size of whites) had a numerically better treatment effect than whites for both doses of SPN-812 ER compared to placebo; similarly, females had a numerically better treatment effect than males. Despite the smaller sample size, SPN-812 ER 400 mg/day showed a numerically better treatment effect in patients ages 15 to 17 years than in those ages 12 to 14 years. Conversely, SPN-812 ER 600 mg/day in patients ages 15 to 17 years showed a numerically worse treatment effect than in those ages 12 to 14 years.

Study 301

Table 156. Study 301 Subgroup Analysis by Race: ADHD-RS-5 Total Score (ITT) LS◊ Mean Change LS◊ Mean Difference Baseline from Baseline from Placebo Treatment Group N Mean (SD*) N Mean SE# Mean SE# White Placebo 77 43.0 (7.62) 73 -10.6 1.64 -- -- SPN-812 ER 100 mg/day 76 45.1 (6.46) 73 -17.9 1.66 -7.2 2.33 SPN-812 ER 200 mg/day 83 44.0 (7.09) 80 -18.4 1.58 -7.8 2.27

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LS◊ Mean Change LS◊ Mean Difference Baseline from Baseline from Placebo Treatment Group N Mean (SD*) N Mean SE# Mean SE# Non-white Placebo 78 44.1 (6.44) 68 -11.5 1.59 -- -- SPN-812 ER 100 mg/day 71 44.9 (6.64) 66 -15.2 1.62 -3.7 2.24 SPN-812 ER 200 mg/day 75 44.0 (6.52) 66 -17.0 1.58 -5.5 2.21 Source: Reviewer-generated * Standard deviation, # standard error, ◊ least squares Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine Table 157. Study 301 Subgroup Analysis by Gender: ADHD-RS-5 Total Score (ITT) LS◊ Mean Change LS◊ Mean Difference Baseline from Baseline from Placebo Treatment Group N Mean (SD*) N Mean SE# Mean SE# Male Placebo 97 43.4 (7.19) 87 -10.6 1.48 -- -- SPN-812 ER 100 mg/day 94 45.2 (6.77) 87 -15.2 1.49 -4.6 2.09 SPN-812 ER 200 mg/day 99 44.4 (6.90) 95 -18.0 1.44 -7.3 2.05 Female Placebo 58 43.8 (6.85) 54 -11.0 1.78 -- -- SPN-812 ER 100 mg/day 53 44.8 (6.13) 52 -18.7 1.84 -7.6 2.51 SPN-812 ER 200 mg/day 59 43.4 (6.65) 51 -17.4 1.77 -6.4 2.48 Source: Reviewer-generated * Standard deviation, # standard error, ◊ least squares Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine Table 158. Study 301 Subgroup Analysis by Age: ADHD-RS-5 Total Score (ITT) LS◊ Mean Change LS◊ Mean Difference Baseline from Baseline from Placebo Treatment Group N Mean (SD*) N Mean SE# Mean SE# Age 6-9 Placebo 103 44.6 (6.22) 92 -9.8 1.44 -- -- SPN-812 ER 100 mg/day 103 45.9 (6.02) 97 -16.5 1.42 -6.7 2.03 SPN-812 ER 200 mg/day 107 44.3 (6.58) 96 -17.5 1.38 -7.7 2.01 Age 10-11 Placebo 52 41.4 (8.11) 49 -12.4 1.80 -- -- SPN-812 ER 100 mg/day 44 43.0 (7.24) 42 -16.0 1.96 -3.6 2.67 SPN-812 ER 200 mg/day 51 43.3 (7.27) 50 -17.5 1.81 -5.1 2.56 Source: Reviewer-generated * Standard deviation, # standard error, ◊ least squares Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine

Study 302

Table 159. Study 302 Subgroup Analysis by Race: ADHD-RS-5 Total Score (ITT) LS◊ Mean Change LS◊ Mean Difference Baseline from Baseline from Placebo Treatment Group N Mean (SD*) N Mean SE# Mean SE# White Placebo 63 40.5 (6.64) 62 -12.3 1.73 -- -- SPN-812 ER 200 mg/day 53 40.3 (7.04) 53 -19.7 1.87 -7.3 2.54 SPN-812 ER 400 mg/day 55 38.8 (7.41) 54 -16.5 1.85 -4.1 2.52

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LS◊ Mean Change LS◊ Mean Difference Baseline from Baseline from Placebo Treatment Group N Mean (SD*) N Mean SE# Mean SE# Non-white Placebo 41 40.5 (7.11) 40 -9.9 2.19 -- -- SPN-812 ER 200 mg/day 41 39.4 (7.51) 35 -10.3 2.28 -0.4 3.10 SPN-812 ER 400 mg/day 48 40.0 (7.82) 44 -16.3 2.05 -6.4 2.96 Source: Reviewer-generated * Standard deviation, # standard error, ◊ least squares Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine Table 160. Study 302 Subgroup Analysis by Gender: ADHD-RS-5 Total Score (ITT) LS◊ Mean Change LS◊ Mean Difference Baseline from Baseline from Placebo Treatment Group N Mean (SD*) N Mean SE# Mean SE# Male Placebo 58 40.7 (6.48) 57 -8.70 1.77 -- -- SPN-812 ER 200 mg/day 66 40.2 (7.14) 60 -15.8 1.66 -7.0 2.39 SPN-812 ER 400 mg/day 67 39.3 (7.77) 62 -18.0 1.64 -9.3 2.38 Female Placebo 46 40.3 (7.23) 45 -14.7 2.15 -- -- SPN-812 ER 200 mg/day 28 39.3 (7.52) 28 -16.5 2.77 -1.9 3.50 SPN-812 ER 400 mg/day 36 39.4 (7.35) 36 -13.9 2.43 0.8 3.25 Source: Reviewer-generated * Standard deviation, # standard error, ◊ least squares Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine Table 161. Study 302 Subgroup Analysis by Age: ADHD-RS-5 Total Score (ITT) LS◊ Mean Change LS◊ Mean Difference Baseline from Baseline from Placebo Treatment Group N Mean (SD*) N Mean SE# Mean SE# Age 12-14 Placebo 70 41.6 (6.36) 68 -9.7 1.62 -- -- SPN-812 ER 200 mg/day 63 41.0 (6.80) 58 -16.9 1.73 -7.1 2.37 SPN-812 ER 400 mg/day 64 40.3 (7.37) 60 -16.4 1.71 -6.7 2.36 Age 15-17 Placebo 34 38.3 (7.21) 34 -15.1 2.44 -- -- SPN-812 ER 200 mg/day 31 37.8 (7.70) 30 -14.4 2.57 0.7 3.55 SPN-812 ER 400 mg/day 39 37.8 (7.77) 38 -16.7 2.30 -1.7 3.35 Source: Reviewer-generated * Standard deviation, # standard error, ◊ least squares Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine

Study 303

Table 162. Study 303 Subgroup Analysis by Race: ADHD-RS-5 Total Score (ITT) LS◊ Mean Change from LS◊ Mean Difference Baseline Baseline from Placebo Treatment Group N Mean (SD*) N Mean SE# Mean SE# White Placebo 53 43.8 (6.79) 52 -13.7 2.05 -- -- SPN-812 ER 200 mg/day 54 43.9 (6.27) 51 -20.1 2.07 -6.4 2.90 SPN-812 ER 400 mg/day 52 45.0 (6.65) 49 -20.4 2.12 -6.7 2.92

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LS◊ Mean Change from LS◊ Mean Difference Baseline Baseline from Placebo Treatment Group N Mean (SD*) N Mean SE# Mean SE# Non-white Placebo 44 43.2 (6.86) 40 -9.2 2.08 -- -- SPN-812 ER 200 mg/day 53 43.7 (6.85) 48 -15.0 1.92 -5.8 2.80 SPN-812 ER 400 mg/day 45 45.0 (6.49) 36 -13.9 2.12 -4.7 2.95 Source: Reviewer-generated * Standard deviation, # standard error, ◊ least squares Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine Table 163. Study 303 Subgroup Analysis by Gender: ADHD-RS-5 Total Score (ITT) LS◊ Mean Change from LS◊ Mean Difference Baseline Baseline from Placebo Treatment Group N Mean (SD*) N Mean SE# Mean SE# Female Placebo 36 44.4 (6.95) 35 -13.7 2.52 -- -- SPN-812 ER 200 mg/day 33 44.8 (6.78) 31 -20.3 2.67 -6.6 3.63 SPN-812 ER 400 mg/day 38 43.5 (6.45) 32 -18.3 2.54 -4.6 3.55 Male Placebo 61 43.0 (6.71) 57 -10.8 1.85 -- -- SPN-812 ER 200 mg/day 74 43.4 (6.42) 68 -16.6 1.71 -5.7 2.50 SPN-812 ER 400 mg/day 59 46.0 (6.46) 53 -16.9 1.93 -6.0 2.66 Source: Reviewer-generated * Standard deviation, # standard error, ◊ least squares Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine Table 164. Study 303 Subgroup Analysis by Age: ADHD-RS-5 Total Score (ITT) LS◊ Mean Change from LS◊ Mean Difference Baseline Baseline from Placebo Treatment Group N Mean (SD*) N Mean SE# Mean SE# Age 6-9 Placebo 64 44.0 (6.76) 61 -11.2 1.84 -- -- SPN-812 ER 200 mg/day 71 44.3 (6.40) 64 -17.4 1.79 -6.2 2.56 SPN-812 ER 400 mg/day 68 45.6 (6.29) 59 -18.5 1.83 -7.3 2.60 Age 10-11 Placebo 33 42.7 (6.88) 31 -11.6 2.43 -- -- SPN-812 ER 200 mg/day 36 42.8 (6.78) 35 -17.5 2.32 -5.9 3.36 SPN-812 ER 400 mg/day 29 43.7 (7.04) 26 -14.3 2.63 -2.7 3.58 Source: Reviewer-generated * Standard deviation, # standard error, ◊ least squares Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine

Study 304

Table 165. Study 304 Subgroup Analysis by Race: ADHD-RS-5 Total Score (ITT) LS◊ Mean Change from LS◊ Mean Difference Baseline Baseline from Placebo Treatment Group N Mean (SD*) N Mean SE# Mean SE# White Placebo 64 39.3 (7.64) 62 -15.4 1.70 -- -- SPN-812 ER 400 mg/day 63 40.8 (8.05) 60 -19.6 1.70 -4.2 2.40 SPN-812 ER 600 mg/day 66 40.6 (7.74) 64 -18.1 1.69 -2.7 2.36

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LS◊ Mean Change from LS◊ Mean Difference Baseline Baseline from Placebo Non-white Placebo 32 37.8 (8.88) 27 -8.1 2.26 -- -- SPN-812 ER 400 mg/day 36 41.9 (7.41) 31 -16.4 2.16 -8.3 3.10 SPN-812 ER 600 mg/day 31 38.1 (9.40) 26 -12.9 2.34 -4.8 3.19 Source: Reviewer-generated * Standard deviation, # standard error, ◊ least squares Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine Table 166. Study 304 Subgroup Analysis by Gender: ADHD-RS-5 Total Score (ITT) LS◊ Mean Change from LS◊ Mean Difference Baseline Baseline from Placebo Treatment Group N Mean (SD*) N Mean SE# Mean SE# Male Placebo 61 37.9 (8.22) 56 -12.2 1.76 -- -- SPN-812 ER 400 mg/day 66 42.5 (7.72) 60 -18.4 1.66 -6.2 2.42 SPN-812 ER 600 mg/day 71 40.1 (7.69) 65 -16.9 1.63 -4.7 2.34 Female Placebo 35 40.2 (7.66) 33 -14.8 2.33 -- -- SPN-812 ER 400 mg/day 33 38.7 (7.43) 31 -18.5 2.41 -3.8 3.36 SPN-812 ER 600 mg/day 26 38.9 (10.02) 25 -15.9 2.74 -1.2 3.60 Source: Reviewer-generated * Standard deviation, # standard error, ◊ least squares Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine Table 167. Study 304 Subgroup Analysis by Age: ADHD-RS-5 Total Score (ITT) LS◊ Mean Change from LS◊ Mean Difference Baseline Baseline from Placebo Treatment Group N Mean (SD*) N Mean SE# Mean SE# Age 12-14 Placebo 63 39.5 (8.05) 58 -14.4 1.74 -- -- SPN-812 ER 400 mg/day 61 42.2 (7.95) 55 -18.2 1.78 -3.9 2.50 SPN-812 ER 600 mg/day 72 40.5 (8.71) 66 -18.1 1.63 -3.7 2.38 Age 15-17 Placebo 33 37.3 (8.00) 31 -11.0 2.20 -- -- SPN-812 ER 400 mg/day 38 39.6 (7.39) 36 -18.5 2.04 -7.5 3.01 SPN-812 ER 600 mg/day 25 37.9 (6.96) 24 -12.7 2.53 -1.8 3.35 Source: Reviewer-generated * Standard deviation, # standard error, ◊ least squares Abbreviations: ADHD = attention-deficit/hyperactivity disorder; ER = extended release; ITT = intent-to-treat; RS = rating scale; SPN = viloxazine 16.2. Other Special/Subgroup Populations: U.S. versus Non-U.S. All of the studies were conducted in the United States, and so a subgroup exploration of extra-U.S. sites is infeasible.

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16.3. Graphical Exploration of Missing Data Patterns The missing data pattern plots (Figure 43, Figure 44, Figure 45, Figure 46) suggest that the missing at random assumption might be reasonable because the dropouts, within each treatment group, may not depend on unobserved ADHD-RS-5 total scores. Figure 43. Missing Data Patterns (Study 301)

Source: Statistical Reviewer Dropout AE, dropout due to adverse events; dropout by parent, withdrawal by parent/guardian; dropout Else: withdrawal by subject, loss to follow-up, or dropout due to non-compliance Abbreviations: ADHD = attention-deficit/hyperactivity disorder; AE = adverse event; ER = extended release; RS = rating scale

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Figure 44. Missing Data Patterns (Study 302)

Source: Statistical Reviewer Dropout AE, dropout due to adverse events; dropout by parent, withdrawal by parent/guardian; dropout Else: withdrawal by subject, loss to follow-up, or dropout due to non-compliance Abbreviations: ADHD = attention-deficit/hyperactivity disorder; AE = adverse event; ER = extended release; RS = rating scale

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Figure 45. Missing Data Patterns (Study 303)

Source: Statistical Reviewer Dropout AE, dropout due to adverse events; dropout by parent, withdrawal by parent/guardian; dropout Else: withdrawal by subject, loss to follow-up, or dropout due to non-compliance Abbreviations: ADHD = attention-deficit/hyperactivity disorder; AE = adverse event; ER = extended release; RS = rating scale

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Figure 46. Missing Data Patterns (Study 304)

Source: Statistical Reviewer Dropout AE, dropout due to adverse events; dropout by parent, withdrawal by parent/guardian; dropout Else: withdrawal by subject, loss to follow-up, or dropout due to non-compliance Abbreviations: ADHD = attention-deficit/hyperactivity disorder; AE = adverse event; ER = extended release; RS = rating scale

17. Clinical Safety Assessment Additional Information and Assessment

This section includes additional information and analyses that were considered in the overall safety review. Treatment-emergent adverse events (TEAEs) from the phase 3 placebo-controlled studies (812P301, 812P302, 812P303, and 812P304) were analyzed using customized grouped terms developed by the clinical review team. AEs with a high degree of overlap (e.g., abdominal pain and upper abdominal pain) were grouped to ensure that clinically meaningful safety signals 239 Integrated Review Template, version date 2019/10/16

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(b) (4) lists adverse reactions that occurred in ≥2% of viloxazine ER–treated patients (and in whom they were more frequent than in placebo-treated patients). Table 169. Adverse Reactions in ≥2% of Viloxazine ER–Treated Patients (More Frequently than Placebo) in Phase 3 Placebo-Controlled Trials Viloxazine ER 100mg 200mg 400mg All Viloxazine Placebo Body System/ N=154 N=367 N=305 N=826 N=463 Adverse Reaction % % % % % Nervous system disorders Somnolence 12 16 19 16 4 Headache 10 11 12 11 7 Metabolic and nutritional disorders Decreased appetite 5 8 8 7 0.4 Infections and Infestations Upper Respiratory Tract Infection 5 7 8 7 6 Body as a Whole: General disorders Fatigue 4 5 9 6 2 Pyrexia 3 2 1 2 0.2 Gastrointestinal system disorders Abdominal Pain 3 6 7 5 4 Nausea 1 4 7 5 3 Vomiting 5 3 6 4 2 Psychiatric disorders Insomnia 2 5 5 4 1 Irritability 3 2 5 3 1 Source: adae.xpt; Software: Python. Created by the Clinical Data Scientist and Clinical Reviewer. Somnolence: somnolence, lethargy, sedation Headache: headache, migraine, migraine with aura, tension headache Upper respiratory tract infection: nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, viral sinusitis, viral upper respiratory tract infection Abdominal pain: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper Insomnia: initial insomnia, insomnia, middle insomnia, poor quality sleep, sleep disorder, terminal insomnia Abbreviations: ER = extended release

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Adverse Events by System Organ Class

Patients treated with viloxazine ER in the phase 3 placebo-controlled trials were most likely to experience adverse events in the following SOCs: nervous system disorders, gastrointestinal disorders, psychiatric disorders, general disorders and administration site conditions, infections and infestations, metabolism and nutrition disorders, and investigations (Table 170). Table 170. Adverse Events by System Organ Class, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) Patients 6 to 11 Years (Trials 812P301 and Patients 12 to 17 Years (Trials 812P302 and 812P303) 812P304) Total 100 mg 200 mg 400 mg Treatment Placebo 200 mg 400 mg 600 mg Treatment Placebo Treatment Placebo System Organ N=154 N=268 N=100 N=522 N=262 N=99 N=205 N=99 N=403 N=201 N=925 N=463 Class % % % % % % % % % % % % Nervous system 22 24 28 24 6 25 31 30 29 16 27 11 disorders Gastrointestinal 10 13 22 14 10 14 15 19 16 9 15 9 disorders Psychiatric 8 12 23 13 9 7 12 13 11 4 12 7 disorders General disorders and administration 7 9 10 9 3 8 11 11 10 3 9 3 site conditions Infections and 7 12 16 11 12 4 11 11 9 10 10 11 infestations Metabolism and 5 10 9 8 2 5 9 7 8 2 8 2 nutrition disorders Investigations 3 4 842453 4 2 4 2 Respiratory, thoracic and 3 3 4 3 2 0 6 1 3 4 3 3 mediastinal disorders Ear and labyrinth 2 0.4 0 1 0 0 1 0 0.2 1 1 0.2 disorders Injury, poisoning and procedural 1 3 2 3 4 3 2 4 3 3 3 4 complications Cardiac disorders 1 2 1 1 0.4 0 2 1 1 0 1 0.2 Musculoskeletal and connective 1 1 1 1 1 1 2 3 2 1 1 1 tissue disorders 243 Integrated Review Template, version date 2019/10/16 Reference ID: 4698714

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Patients 6 to 11 Years (Trials 812P301 and Patients 12 to 17 Years (Trials 812P302 and 812P303) 812P304) Total 100 mg 200 mg 400 mg Treatment Placebo 200 mg 400 mg 600 mg Treatment Placebo Treatment Placebo System Organ N=154 N=268 N=100 N=522 N=262 N=99 N=205 N=99 N=403 N=201 N=925 N=463 Class % % % % % % % % % % % % Blood and lymphatic system 1 1 0 1 0 0 0 0 0 0 0.3 0 disorders Immune system 1 0.4 1 1 0.4 0 0 0 0 0 0.3 0.2 disorders Skin and subcutaneous 0 1 3 1 2 1 2 1 1 1 1 1 tissue disorders Vascular disorders 0 1 0 0.4 0 0 1 3 1 0 1 0 Eye disorders 0 0.4 0 0.2 0 1 0 0 0.2 0 0.2 0 Reproductive system and breast 0 0.4 0 0.2 0 0 0 0 0 1 0.1 0.2 disorders Surgical and 0 0.4 0 0.2 0 0 0 0 0 0 0.1 0 medical procedures Endocrine 0 0 0 0 0.4 0 0 0 0 0 0 0.2 disorders Renal and urinary 0 0 0 0 0 0 1 1 1 1 0.2 0.2 disorders Source: adae.xpt; Software: Python. Created by the Clinical Data Scientist Abbreviations: N, number of subjects in the treatment arm; n, number of subjects with at least one event

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The most commonly reported nervous system disorders were somnolence, headache, and sedation. The most commonly reported gastrointestinal disorders were nausea, vomiting, and abdominal pain. Psychiatric AEs were closely examined because patients with ADHD are at increased risk of other psychiatric disorders and because psychiatric AEs are associated with exposure to other adrenergic agents. Viloxazine ER–treated patients in the phase 3 controlled studies were more likely than placebo-treated patients to report psychiatric AEs (12.3% versus 6.9%). Table 171 and Table 172 list the psychiatric AEs that occurred in ≥3 patients in the two age groups studied in the phase 3 placebo-controlled studies. Insomnia and irritability were the most common psychiatric AEs in patients ages 6 to 11 years and 12 to 17 years, respectively. Table 171. Psychiatric Adverse Events in ≥3 Patients Ages 6 to 11 Years in Phase 3 Studies and at a Frequency Greater than in Placebo-Treated Patients Adverse Event Treatment (N=522) Placebo (N=262) Insomnia 26 (5%) 5 (2%) Irritability 15 (3%) 4 (2%) Mood swings 5 (1%) 2 (1%) Depressed mood 4 (1%) 0 Nightmare 4 (1%) 1 (0.4%) Source: adae.xpt. Created by the Clinical Reviewer Insomnia: initial insomnia, insomnia, middle insomnia, poor-quality sleep, sleep disorder, terminal insomnia Depressed mood: adjustment disorder with mixed anxiety and depressed mood, depressed mood, depressive symptom Table 172. Psychiatric Adverse Events Occurring in ≥3 Patients Ages 12 to 17 Years in Phase 3 Trials and at a Frequency Greater than in Placebo-Treated Patients Adverse Event Treatment (N=403) Placebo (N=201) Irritability 17 (4%) 2 (1%) Insomnia 14 (4%) 1 (1%) Affect lability 5 (1%) 2 (1%) Anxiety 3 (0.7%) 0 Source: adae.xpt. Created by the Clinical Reviewer Insomnia: initial insomnia, insomnia, middle insomnia, poor quality sleep, sleep disorder, terminal insomnia Anxiety: adjustment disorder with mixed anxiety and depressed mood, anxiety, panic attack, separation anxiety disorder Irritability was reported more commonly in patients receiving viloxazine ER than in those receiving placebo. In addition to irritability, patients reported a constellation of preferred terms suggestive of pediatric depression or mood disturbance. These were affect lability, depressed mood, crying, tearfulness, emotional disorder, emotional poverty, emotional distress, self-esteem decreased, flat affect, mood altered, and mood swings. In the viloxazine ER group, 3.7% reported experiencing at least one of these AEs, compared to 2.6% of the placebo group. Although irritability was more common among viloxazine ER–treated patients, the difference between the viloxazine ER and placebo groups in the frequency of other mood-related AEs was small. The psychiatric AE profile in the phase 2 dose-ranging study (812P202) was comparable to that in the phase 3 studies (Table 173). Insomnia and irritability were the most commonly reported psychiatric AEs.

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Table 173. Psychiatric Adverse Events Occurring in ≥2 Patients in Study 812P202 Total Viloxazine Placebo (N=193) (N=24) Adverse Event n (%) n (%) Insomnia 12 (6) 0 Irritability 8 (4) 0 Agitation 5 (3) 0 Suicidal ideation 4 (2) 0 Tearfulness 4 (2) 0 Aggression 2 (1) 0 Abnormal dreams 2 (1) 0 Source: adae.xpt. Created by the Clinical Reviewer Insomnia: terminal insomnia, middle insomnia, initial insomnia, insomnia Agitation: agitation, anger Psychiatric AEs were commonly reported in the open-label extension study (812P310). Of the 1097 patients treated with viloxazine ER in that study, 155 (14.1%) reported at least one psychiatric AE. Mood-related AEs (preferred terms affective disorder, affect lability, blunted affect, flat affect, irritability, depressed mood, depression, depressive symptom, major depression, mood altered, mood swings, persistent depressive disorder, and tearfulness) were reported by 89 (8.1%) of the patients in Study 812P310. A high rate of psychiatric symptomatology is expected in patients with ADHD. This uncontrolled study is not designed to determine whether the rate of mood-related symptoms is higher in patients treated chronically with viloxazine ER. Of note, no events suggestive of psychosis or mania occurred in the phase 3 placebo-controlled studies. In Study 812P202, confusional state was reported as an AE by one patient. In the open- label safety extension (812P310), the following AEs possibly suggestive of psychosis occurred in 6 (0.5%) patients (ages 7 to 11 years): abnormal behavior (2 patients), hallucination auditory, hallucination visual, psychotic disorder, and confusional state. The lack of a strong psychosis or mania signal may represent a safety advantage of viloxazine ER over stimulant medications and atomoxetine. However, patients with psychosis and mania were specifically excluded in the study, so the effect of viloxazine ER in patients with bipolar or psychotic disorders is unknown. Depressive symptoms co-occur frequently in patients with ADHD and pediatric bipolar disorder may first present as a depressive episode. Therefore, patients receiving viloxazine ER should be carefully screened for risk factors for bipolar disorder prior to treatment. The proposed labeling for viloxazine ER will include a recommendation to screen for bipolar disorder risk factors and a boxed warning regarding the risk of suicidal ideation and behavior. The most frequently occurring psychiatric AEs, irritability, and insomnia, are listed in Section 6.

Adverse Events Leading to Discontinuation

Table 174 provides additional information on the TEAEs that led to discontinuation in the phase 3 controlled studies. Of the 32 AEs leading to discontinuation, 19 occurred within the first 21 days of drug exposure.

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Table 174. Adverse Events Leading to Discontinuation, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) Study Duration of Duration Day of Adverse of AE Event Exposure Study Arm Subject ID Age Sex Preferred Term Verbatim Term SAE1 Onset (Days) (Days) Relatedness2

Placebo- (b) (6) Exacerbation of adolescents 304 16 F Suicidal ideation suicidal ideation N 17 0 16 Not related Placebo- Aggressive children 301 7 M Aggression behavior N 1 5 5 Possibly related Placebo- children 303 9 F Tic Motor tic, facial N 3 6 8 Possibly related Placebo- Emotional children 303 11 F Affect lability meltdown N 21 15 29 Possibly related Placebo- Physical children 303 6 M Aggression aggression N 11 24 14 Possibly related Placebo- children 301 7 M Agitation Agitation N 2 16 11 Possibly related SPN-812 ER 100 mg- children 301 8 F Tachycardia Tachycardia N 14 6 15 Possibly related SPN-812 ER 100 mg- Electrocardiogram Abnormal ecg- children 301 7 F t wave inversion inverted t waves N 14 14 Possibly related SPN-812 ER 100 mg- Arson, inpatient children 301 10 M Pyromania behavioral health Y 2 0 3 Unlikely related SPN-812 ER 100 mg- children 301 11 M Conduct disorder Conduct disorder Y 16 1 15 Unlikely related SPN-812 ER 100 mg- children 301 7 M Aggression Aggression N 1 30 Possibly related SPN-812 ER 200 mg- Definitely adolescents 302 14 F Diarrhoea Diarrhea N 0 3 4 related SPN-812 ER 200 mg- Daytime adolescents 302 17 M Somnolence drowsiness N 2 13 15 Possibly related

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Study Duration of Duration Day of Adverse of AE Event Exposure Study Arm Subject ID Age Sex Preferred Term Verbatim Term SAE1 Onset (Days) (Days) Relatedness2 SPN-812 ER 200 mg- (b) (6) adolescents 302 13 F Syncope Syncopal episode Y 23 0 25 Unlikely related SPN-812 ER 200 mg- adolescents 302 16 M Anxiety Anxiety N 3 4 6 Possibly related SPN-812 ER 200 mg- Decreased children 301 8 M appetite Decreased appetite N 22 1 24 Possibly related SPN-812 ER 200 mg- children 301 10 M Sleep terror Night terrors N 0 10 6 Possibly related SPN-812 ER 200 mg- children 303 7 M Nausea Nausea N 13 13 21 Possibly related SPN-812 ER 200 mg- Hypersensitivity to children 303 9 F Hyperacusis sound N 4 13 15 Possibly related SPN-812 ER 200 mg- children 303 7 M Irritability Irritable N 22 6 29 Possibly related SPN-812 ER 200 mg- Definitely children 303 11 M Hot flush Hot flashes N 0 2 1 related SPN-812 ER 200 mg- children 303 11 M Fatigue Fatigue N 0 32 22 Possibly related SPN-812 ER 200 mg- children 303 7 M Affect lability Emotional lability N 9 18 26 Not related SPN-812 ER 400 mg- Intermittent Definitely adolescents 304 16 M Headache headaches N 1 3 4 related

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Study Duration of Duration Day of Adverse of AE Event Exposure Study Arm Subject ID Age Sex Preferred Term Verbatim Term SAE1 Onset (Days) (Days) Relatedness2 SPN-812 ER

400 mg- (b) (6) Definitely adolescents 302 12 M Terminal insomnia Terminal insomnia N 469related SPN-812 ER 400 mg- adolescents 304 15 M Suicide attempt Suicidal attempt Y 46 0 48 Possibly related SPN-812 ER 400 mg- Abdominal pain Definitely adolescents 304 13 M upper Stomach ache N 5 31 43 related SPN-812 ER 400 mg- adolescents 302 12 F Somnolence Somnolence N 11 8 18 Possibly related SPN-812 ER 400 mg- Intermittent Definitely adolescents 304 12 F Vomiting vomiting N 14 3 18 related SPN-812 ER 400 mg- children 303 6 M Flat affect Flattened affect N 5 7 9 Possibly related SPN-812 ER 400 mg- children 303 6 M Gastroenteritis Gastroenteritis N 21 11 22 Possibly related SPN-812 ER 400 mg- children 303 6 M Sedation Excessive sedation N 7 14 14 Possibly related SPN-812 ER 400 mg- Coarsening of Definitely children 303 8 F Mood altered mood N 0 11 8 related SPN-812 ER 600 mg- adolescents 304 12 M Fatigue Fatigue N 0 27 24 Possibly related SPN-812 ER 600 mg- adolescents 304 14 M Depressed mood Depressed mood N 21 17 35 Possibly related

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Study Duration of Duration Day of Adverse of AE Event Exposure Study Arm Subject ID Age Sex Preferred Term Verbatim Term SAE1 Onset (Days) (Days) Relatedness2 SPN-812 ER 600 mg- Definitely (b) (6) adolescents 304 16 M Somnolence Somnolence N 1 19 30 related SPN-812 ER 600 mg- adolescents 304 14 M Somnolence Sleepiness N 0 7 7 Possibly related SPN-812 ER 600 mg- adolescents 304 13 M Vitiligo Vitiligo-like rash N 22 0 23 Possibly related Source: adae.xpt; Software: Python. Created by the Clinical Data Scientist. 1 SAEs defined as AEs resulting in any of the following: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life- threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 2 Scale of relatedness: not related, possibly related, definitely related, and related. Abbreviations: AE, adverse event; ER = extended release; ID, identification; SAE, serious adverse event; SPN = viloxazine

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Laboratory Assessments—Additional Information

Table 175 and Table 176 list the age-specific reference ranges for laboratory assessments used in the phase 3 controlled studies. Table 175. Laboratory Reference Ranges-Patients Ages 6 to 11 Years Alanine Aminotransferase (U/L) U/L 5 30 Alkaline Phosphatase (U/L) U/L 155 420 Aspartate Aminotransferase (U/L) U/L 0 47 Bilirubin (µmol/L) µmol/L221 Creatinine (µmol/L) µmol/L2168 Glucose (mmol/L) mmol/L 3.9 7.8 Hemoglobin (g/L) g/L 114 151 Leukocytes (10^9/L) 109/L 3.5 10.5 Neutrophils (10^9/L) 109/L 2.1 8.9 Platelets (10^9/L) 109/L 175 420 Potassium (mmol/L) mmol/L 3.5 5.3 Sodium (mmol/L) mmol/L 135 148 Source: ad b.xpt. Created by the Clinical Data Scientist. Table 176. Laboratory Reference Ranges-Patients Ages 12 to 17 Years Alanine Aminotransferase (U/L) U/L 5 20 Alkaline Phosphatase (U/L) U/L 110 630 Aspartate Aminotransferase (U/L) U/L 0 41 Bilirubin (µmol/L) µmol/L221 Creatinine (µmol/L) µmol/L4188 Glucose (mmol/L) mmol/L 3.9 7.8 Hemoglobin (g/L) g/L 113 156 Leukocytes (109/L) 10^9/L 3.5 10.5 Neutrophils (109/L) 10^9/L 2.1 7.8 Platelets (109/L) 10^9/L 140 370 Potassium (mmol/L) mmol/L 3.5 5.3 Sodium (mmol/L) mmol/L 135 148 Source: ad b.xpt. Created by the Clinical Data Scientist. Table 177, Table 178, Table 179, and Table 180 summarize the mean values and mean changes from baseline (by treatment group) in the phase 3 controlled trials. The mean values remained within the normal range. Mean changes from baseline were small and unlikely to be clinically meaningful. Table 177. Laboratory Values1 (Study 812P301) SPN-812 100 mg SPN-812 200 mg SPN-812 Placebo (N=154) (N=161) (N=159) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Alanine Aminotransferase 15.3 15 15.2 (U/L) Baseline 153 (6.5) 161 (5.2) 158 (6.9) Alanine Aminotransferase Week 6 15.8 0.4 16.9 2 15.3 0.1 (U/L) (EOS) 136 (8.3) (7.6) 138 (14.1) (13.8) 139 (5.8) (7) Alkaline Phosphatase 251.9 250.6 249.1 (U/L) Baseline 153 (74) 161 (71) 158 (61.4) 251 Integrated Review Template, version date 2019/10/16

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SPN-812 100 mg SPN-812 200 mg SPN-812 Placebo (N=154) (N=161) (N=159) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Alkaline Phosphatase Week 6 250.5 1.3 249.5 3.2 253.4 5.9 (U/L) (EOS) 136 (69.5) (35.7) 137 (68) (57.9) 137 (63.1) (39.4) Aspartate Aminotransferase 26.4 25.7 25.8 (U/L) Baseline 153 (6.2) 161 (5.3) 158 (5.5) Aspartate Aminotransferase Week 6 26 -0.3 26.5 1 26.1 0.3 (U/L) (EOS) 136 (6.8) (5.1) 138 (16.8) (17.1) 139 (6.3) (5.5) 5.7 5.6 5.9 Bilirubin (umol/L) Baseline 153 (3.6) 161 (3.3) 158 (4) Week 6 5.4 -0.3 5.3 -0.5 5.3 -0.6 Bilirubin (umol/L) (EOS) 136 (2.8) (2.7) 138 (3) (2.5) 139 (2.8) (2.7) Blood Urea 4.3 4.1 4.3 Nitrogen (mmol/L) Baseline 153 (1.2) 161 (1.2) 158 (1.2) Blood Urea Week 6 4.2 -0.2 4.2 0 4.5 0.2 Nitrogen (mmol/L) (EOS) 136 (1.3) (1.2) 138 (1.1) (1.1) 139 (1.3) (1.3) 2.4 2.4 2.4 Calcium (mmol/L) Baseline 153 (0.1) 160 (0.1) 158 (0.1) Week 6 2.4 0 2.4 0 2.4 0 Calcium (mmol/L) (EOS) 136 (0.1) (0.1) 137 (0.1) (0.1) 137 (0.1) (0.1) 100.2 99.8 99.6 Chloride (mmol/L) Baseline 153 (1.9) 161 (2.3) 158 (2.2) Week 6 100.1 -0.2 99.7 -0.1 100 0.4 Chloride (mmol/L) (EOS) 136 (2.1) (2.6) 138 (2.1) (2.6) 139 (2.3) (2.9) Creatinine 43.5 43.6 43.6 (umol/L) Baseline 153 (7.5) 161 (8.2) 158 (8.4) Creatinine Week 6 44.8 1.6 47.1 3.6 44 0.7 (umol/L) (EOS) 136 (7.4) (7.2) 138 (8.9) (9.1) 139 (8.3) (7.6) Direct Bilirubin 3.1 3.1 3.1 (umol/L) Baseline 153 (0.3) 159 (0.3) 158 (0.5) Direct Bilirubin Week 6 3 0 3.1 0 3 0 (umol/L) (EOS) 136 (0.3) (0.3) 138 (0.3) (0.3) 139 (0.3) (0.4) Eosinophils 0.3 0.3 0.2 (10^9/L) Baseline 153 (0.3) 161 (0.4) 159 (0.2) Eosinophils Week 6 0.3 0 0.3 0 0.3 0 (10^9/L) (EOS) 136 (0.4) (0.2) 138 (0.2) (0.2) 139 (0.3) (0.2) 4.9 4.9 4.8 Glucose (mmol/L) Baseline 153 (0.6) 161 (0.7) 158 (0.7) Week 6 4.8 -0.1 4.9 0.1 4.9 0 Glucose (mmol/L) (EOS) 136 (0.7) (0.9) 138 (0.8) (0.9) 138 (0.7) (0.8) Hematocrit 0.4 0.4 0.4 (fraction of 1) Baseline 153 (0) 161 (0) 159 (0) Hematocrit Week 6 0.4 0 0.4 0 0.4 0 (fraction of 1) (EOS) 136 (0) (0) 138 (0) (0) 139 (0) (0) 130.2 130.2 129.3 Hemoglobin (g/L) Baseline 153 (8.9) 161 (9) 159 (9.6) Week 6 129.3 -0.9 131.3 0.1 127.5 -2 Hemoglobin (g/L) (EOS) 136 (9.8) (7.5) 138 (9.5) (7.3) 139 (10) (6.7)

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SPN-812 100 mg SPN-812 200 mg SPN-812 Placebo (N=154) (N=161) (N=159) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Leukocytes 6.4 6.7 6.6 (10^9/L) Baseline 153 (1.9) 161 (1.8) 159 (2.1) Leukocytes Week 6 6.1 -0.4 6.3 -0.4 6.3 -0.4 (10^9/L) (EOS) 136 (1.9) (1.6) 138 (1.9) (2) 139 (1.8) (2.1) Neutrophils 3.2 3.3 3.2 (10^9/L) Baseline 153 (1.4) 161 (1.5) 159 (1.6) Neutrophils Week 6 3 -0.3 3.1 -0.3 2.9 -0.3 (10^9/L) (EOS) 136 (1.3) (1.3) 138 (1.6) (1.8) 139 (1.3) (1.7) 306 312.1 312.7 Platelets (10^9/L) Baseline 153 (61.8) 161 (68.6) 159 (69.4) Week 6 287.9 -15.7 288 -17.5 307.9 -6.8 Platelets (10^9/L) (EOS) 136 (53.1) (45.6) 138 (69.8) (45.3) 139 (65.6) (51.3) Potassium 4.4 4.3 4.4 (mmol/L) Baseline 153 (0.4) 160 (0.4) 158 (0.4) Potassium Week 6 4.3 -0.1 4.4 0.1 4.4 0 (mmol/L) (EOS) 136 (0.4) (0.5) 137 (0.4) (0.5) 137 (0.4) (0.5) 140.2 140 140.1 Sodium (mmol/L) Baseline 153 (1.9) 161 (2.1) 158 (2.1) Week 6 140.1 -0.2 140.2 0.3 140.1 0 Sodium (mmol/L) (EOS) 136 (2.1) (2.6) 138 (1.8) (2.6) 139 (2.3) (2.9) Source: ad b.xpt. Created by the Clinical Data Scientist. 1 Does not include unscheduled visits Abbreviations: EOS = end of study; SPN = viloxazine Table 178. Laboratory Values1 (Study 812P302) SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=99) (N=105) (N=104) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Alanine Aminotransferase 14.8 16.1 14.8 (U/L) Baseline 98 (5) 104 (8.2) 104 (8.9) Alanine Aminotransferase Week 6 15.6 0.8 18.1 1.9 14.6 -0.2 (U/L) (EOS) 86 (7.4) (6.6) 96 (12.4) (11.1) 102 (7.8) (6.4) Alkaline Phosphatase 210.5 207.7 206.2 (U/L) Baseline 98 (112.9) 103 (104.9) 104 (113) Alkaline Phosphatase Week 6 207 -4.5 197.7 -5.6 201.1 -2.1 (U/L) (EOS) 86 (106.8) (34.3) 95 (104) (31.9) 101 (109.6) (41.6) 8.7 7.2 8.1 Bilirubin (µmol/L) Baseline 98 (6) 104 (5.7) 104 (6.4) Week 6 8.1 -0.7 6.2 -1.2 7.9 -0.3 Bilirubin (µmol/L) (EOS) 86 (7.4) (6.3) 96 (5) (3.6) 102 (6.9) (4.1) Aspartate Aminotransferase 21.3 21.5 20.4 (U/L) Baseline 98 (5.8) 104 (6.2) 104 (6.2)

253 Integrated Review Template, version date 2019/10/16

Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=99) (N=105) (N=104) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Aspartate Aminotransferase Week 6 21.3 -0.3 21.5 0.2 20 -0.4 (U/L) (EOS) 86 (6.4) (4.8) 96 (7.3) (7.5) 102 (5.8) (4.7) Blood Urea Nitrogen 3.7 4.2 4.1 (mmol/L) Baseline 98 (1) 104 (1.4) 104 (1.1) Blood Urea Nitrogen Week 6 4 0.2 4 -0.2 4 -0.1 (mmol/L) (EOS) 86 (1) (1.1) 96 (1.2) (1.5) 102 (1.3) (1.3) 2.4 2.4 2.4 Calcium (mmol/L) Baseline 98 (0.1) 103 (0.1) 104 (0.1) Week 6 2.4 0 2.4 0 2.4 0 Calcium (mmol/L) (EOS) 86 (0.1) (0.1) 95 (0.1) (0.1) 101 (0.1) (0.1) 100.5 99.8 100.5 Chloride (mmol/L) Baseline 98 (2) 104 (2.8) 104 (2.2) Week 6 100 -0.5 100.5 0.7 100.6 0.1 Chloride (mmol/L) (EOS) 86 (2.1) (2.4) 97 (2.1) (3.3) 102 (2.2) (2.8) Creatinine 61 59.6 58.2 (µmol/L) Baseline 98 (12.4) 104 (13.8) 104 (12.6) Creatinine Week 6 64.4 3.1 65.2 5.7 57.5 -0.6 (µmol/L) (EOS) 86 (12.7) (6.9) 96 (17.5) (15.8) 102 (11.8) (7.8) Direct Bilirubin 3.3 3.2 3.2 (µmol/L) Baseline 98 (0.7) 104 (0.6) 104 (0.7) Direct Bilirubin Week 6 3.2 -0.1 3.1 -0.1 3.2 0 (µmol/L) (EOS) 86 (0.6) (0.7) 95 (0.4) (0.6) 102 (0.6) (0.7) Eosinophils 0.2 0.2 0.2 (109/L) Baseline 99 (0.2) 105 (0.2) 104 (0.2) Eosinophils Week 6 0.2 0 0.3 0 0.2 0 (109/L) (EOS) 87 (0.1) (0.1) 97 (0.5) (0.4) 101 (0.2) (0.1) 5 4.8 4.9 Glucose (mmol/L) Baseline 98 (0.7) 104 (0.6) 104 (0.7) Week 6 5.2 0.2 4.9 0.1 5 0.1 Glucose (mmol/L) (EOS) 86 (0.8) (0.9) 96 (0.7) (0.8) 102 (0.7) (0.8) Hematocrit 0.4 0.4 0.4 (fraction of 1) Baseline 99 (0) 105 (0) 104 (0) Hematocrit Week 6 0.4 0 0.4 0 0.4 0 (fraction of 1) (EOS) 87 (0) (0) 97 (0) (0) 101 (0) (0) 138.8 138.9 136.2 Hemoglobin (g/L) Baseline 99 (13.8) 105 (13) 104 (12) Week 6 137.8 -1.9 138.4 -0.9 134 -2.4 Hemoglobin (g/L) (EOS) 87 (13.3) (8.9) 97 (13.1) (7.4) 101 (12) (6.8) Leukocytes 6.3 6.3 6.2 (109/L) Baseline 99 (2) 105 (1.9) 104 (1.8) Leukocytes Week 6 6.1 -0.3 6.1 -0.3 6.1 -0.1 (109/L) (EOS) 87 (1.7) (1.5) 97 (1.9) (1.6) 101 (1.9) (1.5) Neutrophils 3.5 3.3 3.3 (109/L) Baseline 99 (1.6) 105 (1.5) 104 (1.4) Neutrophils Week 6 3.2 -0.3 3.2 -0.1 3.2 -0.1 (109/L) (EOS) 87 (1.3) (1.2) 97 (1.4) (1.5) 101 (1.5) (1.2)

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=99) (N=105) (N=104) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) 272.2 277.3 276.6 Platelets (109/L) Baseline 99 (72.4) 105 (55.4) 104 (54.4) Week 6 267.9 -4.7 269 -9.2 274.2 -3 Platelets (109/L) (EOS) 87 (63.2) (50.9) 97 (53.5) (40.8) 101 (57.1) (33.4) Potassium 4.5 4.5 4.5 (mmol/L) Baseline 98 (0.4) 103 (0.5) 104 (0.4) Potassium Week 6 4.4 -0.1 4.5 -0.1 4.5 0 (mmol/L) (EOS) 86 (0.5) (0.5) 96 (0.5) (0.5) 101 (0.4) (0.6) 141.1 140.4 140.9 Sodium (mmol/L) Baseline 98 (1.8) 104 (2.4) 104 (2) Week 6 140.7 -0.5 140.9 0.4 140.5 -0.4 Sodium (mmol/L) (EOS) 86 (1.8) (2.2) 97 (1.9) (2.9) 102 (1.9) (2.4) Source: ad b.xpt. Created by the Clinical Data Scientist. 1 Does not include unscheduled visits Abbreviations: EOS = end of study; SPN = viloxazine Table 179. Laboratory Values1 (Study 812P303) SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=107) (N=100) (N=103) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Alanine Aminotransferase 14.4 15 15.7 (U/L) Baseline 107 (4.9) 100 (6.1) 103 (6.3) Alanine Aminotransferase Week 8 15.1 0.7 16.2 1.1 15.6 -0.3 (U/L) (EOS) 97 (6) (6.1) 81 (10.5) (8.4) 92 (6.6) (7.1) Alkaline Phosphatase 240.2 253.6 238 (U/L) Baseline 107 (63.5) 100 (76.8) 103 (55.2) Alkaline Phosphatase Week 8 240.7 5.5 247 -1.8 246.5 11.5 (U/L) (EOS) 97 (65.8) (42.9) 81 (67.3) (52.7) 92 (60.5) (39.6) Aspartate Aminotransferase 25.8 26 26.8 (U/L) Baseline 107 (5.4) 100 (5.2) 103 (6) Aspartate Aminotransferase Week 8 26.5 0.8 25.8 -0.2 26.3 -0.4 (U/L) (EOS) 97 (8.6) (7.7) 81 (6.4) (5.4) 92 (6.5) (5.5) 5.5 6.1 5.8 Bilirubin (µmol/L) Baseline 107 (3.2) 100 (3.5) 103 (3.2) Week 8 4.8 -0.7 5.7 -0.8 5.9 0.5 Bilirubin (µmol/L) (EOS) 97 (2.4) (2.8) 81 (3.7) (2.9) 92 (3.6) (2.5) Blood Urea 4.4 4.3 4.3 Nitrogen (mmol/L) Baseline 107 (1.4) 100 (1.2) 103 (1) Blood Urea Week 8 4.4 0 4.4 0 4.6 0.3 Nitrogen (mmol/L) (EOS) 97 (1.3) (1.4) 81 (1.3) (1.3) 92 (1.2) (1.2) 2.4 2.4 2.4 Calcium (mmol/L) Baseline 107 (0.1) 100 (0.1) 103 (0.1)

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=107) (N=100) (N=103) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Week 8 2.4 0 2.4 0 2.4 0 Calcium (mmol/L) (EOS) 97 (0.1) (0.1) 81 (0.1) (0.1) 92 (0.1) (0.1) 100 99.9 99.9 Chloride (mmol/L) Baseline 107 (1.9) 100 (1.8) 103 (1.9) Week 8 100 0.1 100 0.1 100.6 0.8 Chloride (mmol/L) (EOS) 97 (2.5) (2.5) 81 (1.9) (2) 92 (2.8) (2.9) Creatinine 44 43.5 42.9 (µmol/L) Baseline 107 (7.5) 100 (10.4) 103 (7.5) Creatinine Week 8 45.8 1.5 47.3 4.2 45.3 2 (µmol/L) (EOS) 97 (8) (5.8) 81 (13.4) (14.2) 92 (8.7) (7.3) Direct Bilirubin 3 3.1 3.1 (µmol/L) Baseline 107 (0.2) 100 (0.3) 103 (0.4) Direct Bilirubin Week 8 3 0 3.1 0 3.1 0 (µmol/L) (EOS) 97 (0.1) (0.2) 81 (0.4) (0.4) 92 (0.4) (0.4) Eosinophils 0.3 0.3 0.3 (109/L) Baseline 106 (0.3) 100 (0.3) 102 (0.3) Eosinophils Week 8 0.3 0 0.2 0 0.3 0 (109/L) (EOS) 98 (0.2) (0.2) 81 (0.2) (0.2) 92 (0.4) (0.3) 4.8 4.8 4.8 Glucose (mmol/L) Baseline 107 (0.7) 100 (0.7) 103 (0.6) Week 8 4.9 0.2 4.9 0 4.8 0 Glucose (mmol/L) (EOS) 97 (0.6) (0.9) 81 (0.9) (1.1) 92 (0.6) (0.9) Hematocrit 0.4 0.4 0.4 (fraction of 1) Baseline 106 (0) 100 (0) 102 (0) Hematocrit Week 8 0.4 0 0.4 0 0.4 0 (fraction of 1) (EOS) 98 (0) (0) 81 (0) (0) 92 (0) (0) 129.2 130.6 131.1 Hemoglobin (g/L) Baseline 106 (9.7) 100 (8.4) 102 (8.1) Week 8 127.7 -1.8 131.5 0.8 129.4 -1.7 Hemoglobin (g/L) (EOS) 98 (9.4) (6.9) 81 (9.9) (9.9) 92 (9.1) (6) Leukocytes 6.2 6.7 6.3 (109/L) Baseline 106 (1.8) 100 (2.1) 102 (2) Leukocytes Week 8 6.4 0.1 6.1 -0.5 6.3 -0.1 (109/L) (EOS) 98 (2.1) (2) 81 (1.9) (1.6) 92 (2.1) (2) Neutrophils 2.9 3.2 3 (109/L) Baseline 106 (1.3) 100 (1.3) 102 (1.6) Neutrophils Week 8 3 0.1 2.8 -0.4 3 0 (109/L) (EOS) 98 (1.7) (1.8) 81 (1.2) (1.3) 92 (1.6) (1.8) 311.6 312.5 314.8 Platelets (109/L) Baseline 106 (67.3) 100 (67) 102 (67.1) Week 8 288.6 -21.3 287.9 -23.6 303.2 -12 Platelets (109/L) (EOS) 98 (67.1) (54.1) 81 (63.9) (54.8) 92 (60.6) (53.3) Potassium 4.5 4.4 4.5 (mmol/L) Baseline 107 (0.4) 100 (0.4) 103 (0.4) Potassium Week 8 4.4 -0.1 4.3 -0.1 4.4 -0.1 (mmol/L) (EOS) 97 (0.4) (0.5) 81 (0.4) (0.4) 92 (0.4) (0.4)

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=107) (N=100) (N=103) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) 140.1 140 139.9 Sodium (mmol/L) Baseline 107 (1.9) 100 (1.9) 103 (1.9) Week 8 140.1 0.1 140.1 0.2 140.2 0.4 Sodium (mmol/L) (EOS) 97 (2.2) (2.5) 81 (2) (2.2) 92 (2.1) (2.4) Source: ad b.xpt. Created by the Clinical Data Scientist. 1 Does not include unscheduled visits Abbreviations: EOS = end of study; SPN = viloxazine Table 180. Laboratory Values1 (Study 812P304) SPN-812 400 mg SPN-812 600 mg SPN-812 Placebo (N=100) (N=99) (N=97) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Alanine Aminotransferase 15.1 14.6 14.2 (U/L) Baseline 100 (8.1) 99 (5.6) 97 (7.9) Alanine Aminotransferase Week 7 20.2 5 16.9 2.3 13.9 -0.5 (U/L) (EOS) 86 (16.5) (16.2) 88 (9.6) (9.6) 88 (6.6) (5.2) Alkaline Phosphatase 206.8 223.3 204.1 (U/L) Baseline 100 (116.5) 99 (106.3) 97 (114.4) Alkaline Phosphatase Week 7 207.2 3.1 219.5 2.6 194.1 -8.6 (U/L) (EOS) 86 (118.3) (36.6) 88 (109.1) (28.8) 88 (108.6) (31.9) Aspartate Aminotransferase 21.1 21.4 20.2 (U/L) Baseline 100 (6.2) 99 (5.4) 97 (5.5) Aspartate Aminotransferase Week 7 23.1 2.3 20.9 -0.1 19.5 -0.5 (U/L) (EOS) 86 (8.8) (9) 88 (6.5) (5.6) 88 (5.4) (4) 7.6 8.3 8 Bilirubin (µmol/L) Baseline 100 (4.3) 99 (4.6) 97 (5.3) Week 7 6.2 -1.4 6.6 -1.8 7.7 -0.2 Bilirubin (µmol/L) (EOS) 86 (3.6) (3.4) 88 (3.7) (3.5) 88 (4.5) (3.8) Blood Urea Nitrogen 3.9 4 3.9 (mmol/L) Baseline 100 (1) 99 (1.1) 97 (1) Blood Urea Nitrogen Week 7 3.8 0 3.9 -0.2 4.2 0.3 (mmol/L) (EOS) 86 (1.2) (1.1) 88 (1.1) (1.2) 88 (1.2) (1.2) 2.4 2.4 2.4 Calcium (mmol/L) Baseline 100 (0.1) 99 (0.1) 97 (0.1) Week 7 2.4 0 2.4 0 2.4 0 Calcium (mmol/L) (EOS) 86 (0.1) (0.1) 88 (0.1) (0.1) 88 (0.1) (0.1) Chloride 100.7 100.6 100.5 (mmol/L) Baseline 100 (2) 99 (2.2) 97 (2.5) Chloride Week 7 101 0.3 100.6 0.1 100.8 0.1 (mmol/L) (EOS) 86 (2.2) (2.5) 88 (2.1) (2.7) 88 (2.2) (2.7)

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

SPN-812 400 mg SPN-812 600 mg SPN-812 Placebo (N=100) (N=99) (N=97) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Creatinine 59.4 58.7 58.9 (µmol/L) Baseline 100 (13.7) 99 (11.9) 97 (12.2) Creatinine Week 7 61 1.6 61.3 2.6 59.4 0.5 (µmol/L) (EOS) 86 (13.7) (8.6) 88 (13.2) (9.6) 88 (12.8) (8.7) Direct Bilirubin 3.1 3.2 3.2 (µmol/L) Baseline 100 (0.6) 99 (0.6) 97 (0.6) Direct Bilirubin Week 7 3.8 0.7 3.1 -0.1 3.2 0 (µmol/L) (EOS) 86 (7.1) (7) 88 (0.3) (0.4) 88 (0.6) (0.5) Eosinophils 0.3 0.2 0.2 (109/L) Baseline 100 (0.2) 99 (0.2) 96 (0.2) Eosinophils Week 7 0.2 0 0.2 0 0.2 0 (109/L) (EOS) 88 (0.2) (0.1) 88 (0.2) (0.2) 86 (0.2) (0.2) 4.9 5 4.8 Glucose (mmol/L) Baseline 100 (0.6) 99 (0.7) 97 (0.7) Week 7 4.8 0 4.9 -0.1 5 0.1 Glucose (mmol/L) (EOS) 86 (1) (1.1) 88 (0.8) (1.1) 88 (0.7) (0.8) Hematocrit 0.4 0.4 0.4 (fraction of 1) Baseline 100 (0) 99 (0) 96 (0) Hematocrit Week 7 0.4 0 0.4 0 0.4 0 (fraction of 1) (EOS) 88 (0) (0) 88 (0) (0) 86 (0) (0) 136.4 138.9 136.8 Hemoglobin (g/L) Baseline 100 (13.9) 99 (10.5) 96 (11.8) Week 7 137.2 0.6 140.2 0.9 134 -2.3 Hemoglobin (g/L) (EOS) 88 (15.5) (7.7) 88 (12.1) (6.6) 86 (12.2) (7) Leukocytes 6.4 6.5 6.4 (109/L) Baseline 100 (1.9) 99 (1.9) 96 (1.8) Leukocytes Week 7 6.2 -0.3 6.1 -0.5 6.2 -0.3 (109/L) (EOS) 88 (1.7) (1.8) 88 (1.5) (1.9) 86 (1.6) (1.6) Lymphocytes 2.3 2.3 2.2 (109/L) Baseline 100 (0.7) 99 (0.7) 96 (0.6) Lymphocytes Week 7 2.3 -0.1 2.2 -0.1 2.1 -0.1 (109/L) (EOS) 88 (0.8) (0.6) 88 (0.7) (0.7) 86 (0.5) (0.5) Neutrophils 3.3 3.5 3.5 (109/L) Baseline 100 (1.6) 99 (1.7) 96 (1.6) Neutrophils Week 7 3.1 -0.2 3.2 -0.4 3.4 -0.2 (109/L) (EOS) 88 (1.3) (1.5) 88 (1.2) (1.7) 86 (1.3) (1.4) 285.4 277.6 282.1 Platelets (109/L) Baseline 100 (71.7) 99 (57.7) 96 (68.1) Week 7 269.9 -10.9 269.1 -8.3 282.4 -2.5 Platelets (109/L) (EOS) 88 (59.5) (37.6) 88 (51.5) (36.1) 86 (65.5) (35.5) Potassium 4.4 4.4 4.5 (mmol/L) Baseline 100 (0.4) 99 (0.4) 97 (0.4) Potassium Week 7 4.4 0 4.4 0 4.4 0 (mmol/L) (EOS) 86 (0.4) (0.4) 88 (0.4) (0.5) 88 (0.4) (0.5)

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Reference ID: 4698714 NDA 211964 Viloxazine extended-release capsules

SPN-812 400 mg SPN-812 600 mg SPN-812 Placebo (N=100) (N=99) (N=97) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) 140.3 140.7 140.8 Sodium (mmol/L) Baseline 100 (1.8) 99 (2) 97 (2.1) Week 7 140.4 0.1 140.6 -0.2 140.3 -0.6 Sodium (mmol/L) (EOS) 86 (1.7) (2.3) 88 (2.1) (2.7) 88 (1.9) (2.5) Source: ad b.xpt. Created by the Clinical Data Scientist. 1 Does not include unscheduled visits Abbreviations: EOS = end of study; SPN = viloxazine The review team also conducted an analysis of the percentage of patients in each treatment group with out-of-range laboratory values and the percentage of patients whose laboratory values shifted from within to below or above the normal range. Patients receiving viloxazine ER in the controlled phase 3 clinical studies were more likely to experience a shift in liver transaminases from within to greater than the upper limit of the reference range (Table 37). Otherwise, no clinically meaningful effect on laboratory parameters was evident with viloxazine ER exposure. The mean changes in laboratory parameters over the course of the long-term safety extension study (812P310) were small. Table 181 lists the mean changes from baseline in laboratory parameters at month 12. Table 181. Laboratory Parameters by Visit, Safety Population (Study 812P310) Median Mean Change Change from Sample Median from Baseline Parameter Visit1 Size Mean (SD) (Min, Max) Baseline (SD) (Min, Max) Alanine 16 -1 Month 12 71 17.4 (7.3) -0.7 (5.9) aminotransferase (U/L) (7, 44) (-17, 12) 46 -1 Month 12 71 45.8 (2.5) -1 (3.3) Albumin (g/L) (40, 51) (-11, 7) Alkaline Phosphatase 237 11 Month 12 71 247.5 (85.4) 7.9 (56.9) (U/L) (78, 468) (-171, 198) Aspartate 25 0 Month 12 71 24.9 (6.2) 0.1 (6.1) aminotransferase (U/L) (12, 44) (-13, 24) 0.1 0 Month 12 71 0.1 (0.1) 0 (0.1) Basophils (109/L) (0, 0.1) (-0.3, 0.1) 20 -1 Month 12 11 20.4 (2.4) -1.1 (2.6) Bicarbonate (mmol/L) (17, 25) (-6, 2) 4 0 Month 12 71 4.7 (2.2) -0.2 (1.9) Bilirubin (µmol/L) (3, 14) (-6, 5) Blood Urea Nitrogen 3.9 -0.5 Month 12 71 4 (1) -0.5 (1.2) (mmol/L) (2, 6.8) (-2.7, 2.3) 2.4 -0.1 Month 12 71 2.4 (0.1) -0.1 (0.1) Calcium (mmol/L) (2.2, 2.7) (-0.4, 0.2) 49 1 Month 12 71 49.6 (10.4) -0.7 (8.2) Creatinine (µmol/L) (32, 84) (-37, 19) 3 1 Month 12 71 3 (0) 0.6 (1.3) Direct bilirubin (µmol/L) (3, 3) (-7, 1) 0.1 0 Month 12 71 0.2 (0.2) 0 (0.2) Eosinophils (109/L) (0, 0.9) (-0.6, 0.6)

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Median Mean Change Change from Sample Median from Baseline Parameter Visit1 Size Mean (SD) (Min, Max) Baseline (SD) (Min, Max) 4.6 -0.1 Month 12 71 4.6 (0.4) -0.1 (0.3) Erythrocytes (1012/L) (3.7, 5.4) (-0.7, 0.6) 4.8 -0.2 Month 12 71 5 (0.9) -0.1 (1.2) Glucose (mmol/L) (1.7, 7.1) (-3.5, 3.8) 42 1 Month 12 71 42.3 (3.8) 0.6 (3.1) Hematocrit (%) (33, 52) (-6, 8) 132 3 Month 12 71 133.4 (11.2) 2.2 (7.9) Hemoglobin (g/L) (104, 161) (-16, 25) 6 0.3 Month 12 71 6.2 (2) 0.4 (1.8) Leukocytes (109/L) (2.8, 12.9) (-3.3, 6.4) 2.2 0.1 Month 12 71 2.3 (0.7) 0 (0.5) Lymphocytes (109/L) (1.1, 3.9) (-1.2, 1.9) 0.4 0.1 Month 12 71 0.4 (0.2) 0.1 (0.2) Monocytes (109/L) (0, 1.3) (-0.2, 0.9) 3 0.1 Month 12 71 3.3 (1.7) 0.3 (1.6) Neutrophils (109/L) (1, 9.7) (-3.7, 7.1) 1.6 0 Month 12 59 1.6 (0.2) 0.1 (0.2) Phosphate (mmol/L) (1, 2.1) (-0.4, 0.5) 257 -7.5 Month 12 71 264.5 (61.4) -3.4 (50.7) Platelets (109/L) (140, 456) (-143, 157) 4.4 0.1 Month 12 71 4.5 (0.4) 0.1 (0.5) Potassium (mmol/L) (3.8, 5.4) (-1.2, 1.3) 69 -1 Month 12 71 69 (3.7) -1.5 (4.8) Protein (g/L) (62, 79) (-14, 9) 141 1 Month 12 71 141 (2.4) 1.4 (2.8) Sodium (mmol/L) (136, 149) (-4, 11) Source: ad b.xpt; Software, Reviewer modified. 1 Unscheduled visits were not included

Electrocardiograms

The mean increases in heart rate with viloxazine ER exposure as measured by ECG were similar to those in vital signs. Viloxazine ER was not associated with clinically meaningful changes in corrected QT interval or other ECG parameters (Table 182, Table 183, Table 184, and Table 185). Table 182. Electrocardiogram Values1 (Study 812P301) SPN-812 100 mg SPN-812 200 mg SPN-812 Placebo (N=154) (N=161) (N=159) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Heart Rate 79 77.7 78.5 (bpm) Baseline 154 (11.2) 161 (11.5) 159 (10.3) Heart Rate Week 6 81 2.2 81.8 4.5 78.5 0.4 (bpm) (EOS) 139 (11.8) (10.6) 146 (13) (11.9) 142 (10.1) (9.2) PR Interval 137.8 137.4 138.3 (msec) Baseline 154 (17.2) 161 (20.4) 158 (20.2) PR Interval Week 6 136.2 -0.9 136.8 -0.8 139.6 1.4 (msec) (EOS) 138 (16.2) (10.3) 146 (16.9) (13.6) 142 (21.3) (12.5)

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SPN-812 100 mg SPN-812 200 mg SPN-812 Placebo (N=154) (N=161) (N=159) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) QRS Duration 82.2 80.3 81.2 (msec) Baseline 154 (8.7) 161 (8.9) 159 (9.9) QRS Duration Week 6 82.5 -0.2 81.9 0.8 81.6 0.1 (msec) (EOS) 139 (9.6) (6.5) 146 (8.9) (6.7) 142 (9.2) (7.3) QT Interval 363.3 365.3 363.1 (msec) Baseline 154 (23.2) 161 (28.8) 159 (21.4) QT Interval Week 6 359.7 -4.1 357.5 -9 363.5 0 (msec) (EOS) 139 (26.9) (19.2) 146 (27.6) (22) 142 (22.2) (16.3) QTcF Interval 396.5 396 395.5 (msec) Baseline 154 (15.5) 161 (19.1) 159 (14.1) QTcF Interval Week 6 395.4 -1.3 394.2 -2.4 396.2 0.7 (msec) (EOS) 139 (17.4) (12.9) 146 (18.9) (15.9) 142 (15.4) (12.2) Source: adeg.xpt. Created by the Clinical Data Scientist. 1 Does not include unscheduled visits Reference ranges: Heart rate, 60 to 140 bpm; PR interval, 90 to 170 msec; QRS duration, 40 to 90 msec Abbreviations: EOS = end of study; SPN = viloxazine Table 183. Electrocardiogram Values1 (Study 812P302) SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=99) (N=105) (N=104) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Heart Rate 71 67.5 71.5 Baseline 99 105 104 (bpm) (10.3) (10.2) (11.5)

Heart Rate Week 6 75.9 4.5 74.9 7.4 71.2 -0.5 89 97 102 (bpm) (EOS) (13.1) (12.6) (12.2) (11.4) (10.9) (11.1)

PR Interval 142.5 146.3 145.1 Baseline 98 105 103 (ms) (17) (21.5) (17.5)

PR Interval Week 6 142.4 0.2 144.5 -1.9 144.8 -0.4 89 97 102 (ms) (EOS) (18.4) (13.1) (18.3) (11.9) (18.5) (13.5) QRS 89 87.2 86 Duration Baseline 99 105 104 (9.3) (8.9) (8.5) (msec) QRS Week 6 90 1.1 88.1 0.9 87.1 1.2 Duration 89 97 102 (EOS) (8.2) (7) (9.3) (8.1) (10.1) (7.1) (msec) QT Interval 379.3 386.1 380 Baseline 99 105 104 (msec) (26.9) (27.7) (28.7)

QT Interval Week 6 370.7 -8.4 369.2 -16.9 378 -1.4 89 97 102 (msec) (EOS) (28.1) (23.4) (28.4) (24.6) (27.4) (24.9)

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SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=99) (N=105) (N=104) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) QTcF Interval 399.5 399.8 400.8 Baseline 99 105 104 (msec) (19.9) (20.2) (17.7)

QTcF Interval Week 6 398.5 -1.7 395.3 -4.5 398.4 -2.1 89 97 102 (msec) (EOS) (17.8) (14.3) (17.4) (15.4) (18.3) (15.4) Source: adeg.xpt. Created by the Clinical Data Scientist. 1 Does not include unscheduled visits Reference ranges: Heart rate, 50 to 130 bpm; PR interval, 90 to 200 msec; QRS duration, 40 to 100 msec Abbreviations: EOS = end of study; SPN = viloxazine Table 184. Electrocardiogram Values1 (Study 812P303) SPN-812 200 mg SPN-812 400 mg SPN-812 Placebo (N=107) (N=100) (N=103) Mean Mean Mean Change Mean Mean Change Parameter Visit N (SD) (SD) N Mean ChangeN (SD) (SD) Heart Rate 76 77.5 77.8 Baseline 107 100 103 (bpm) (11.7) (11.5) (12.4)

Heart Rate Week 8 79.3 3.8 82.5 4.9 79 0.2 99 83 93 (bpm) (EOS) (12.5) (11.1) (14.8) (14.3) (10) (12.6)

PR Interval 135.2 138.2 138.4 Baseline 106 99 101 (msec) (17.4) (18.4) (17.1)

PR Interval Week 8 135.5 0.3 136.5 -2.6 138.7 1 99 83 93 (msec) (EOS) (16.4) (11.2) (18.5) (14.3) (17.3) (12.4) QRS 82.2 83.4 81.9 Duration Baseline 107 100 103 (8.9) (9.4) (8.3) (msec) QRS Week 8 83.4 0.9 83.7 0.5 82.4 0.9 Duration 99 83 93 (EOS) (8.8) (5.9) (8.1) (6.6) (8.1) (5.2) (msec) QT Interval 374 370.5 369 Baseline 107 100 103 (msec) (28.9) (27.6) (26)

QT Interval Week 8 367.2 -7.9 361.7 -8.2 365.9 -1.7 99 83 93 (msec) (EOS) (31.3) (24.8) (32.3) (30.3) (25.6) (26.4)

QTcF Interval 402.4 401.4 400.3 Baseline 107 100 103 (msec) (18.5) (18.8) (18)

QTcF Interval Week 8 400.4 -2.3 399 -1.8 399.4 -1 99 83 93 (msec) (EOS) (20.3) (15.3) (18.2) (16.8) (17.2) (16.5) Source: adeg.xpt. Created by the Clinical Data Scientist. 1 Does not include unscheduled visits Reference ranges: Heart rate, 60 to 140 bpm; PR interval, 90 to 170 msec; QRS duration, 40 to 90 msec Abbreviations: EOS = end of study; SPN = viloxazine

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Table 185. Electrocardiogram Values1 (Study 812P304) SPN-812 400 mg SPN-812 600 mg SPN-812 Placebo (N=100) (N=99) (N=97) Mean Mean Mean Mean Change Mean Change Mean Change Parameter Visit N (SD) (SD) N (SD) (SD) N (SD) (SD) Heart Rate 70.8 69.9 69.1 Baseline 100 99 97 (bpm) (12.1) (11.5) (10.9)

Heart Rate Week 7 76.7 5.7 78.1 7 69.1 -0.4 91 90 89 (bpm) (EOS) (14.3) (10.9) (12.7) (11.8) (12) (11.8)

PR Interval 143.8 140.1 145.1 Baseline 99 99 97 (msec) (18.5) (19.2) (21.4)

PR Interval Week 7 142.5 -0.8 141 0.3 144.6 0.3 91 89 89 (msec) (EOS) (20.2) (13.2) (17) (14.9) (20.5) (12.8) QRS 89.8 89.5 88.6 Duration Baseline 100 99 97 (8) (8.4) (9.3) (msec) QRS Week 7 89.1 -0.8 89.1 -0.2 89.6 1 Duration 91 90 89 (EOS) (7.9) (6.9) (8.3) (6.2) (10.9) (6.4) (msec) QT Interval 382.9 385.3 387.1 Baseline 100 99 97 (msec) (25.4) (29.3) (27.8)

QT Interval Week 7 372.3 -10 367.8 -14.7 387 1 91 90 89 (msec) (EOS) (29.4) (23.7) (27.9) (25.6) (27.9) (25.3)

QTcF Interval 402.2 402.8 403.6 Baseline 100 99 97 (msec) (17.6) (16.7) (18)

QTcF Interval Week 7 401 -1.1 398.9 -3.6 403.3 -0.1 91 90 89 (msec) (EOS) (18.5) (16.1) (16.5) (16.9) (21.1) (15.8) Source: adeg.xpt. Created by the Clinical Data Scientist. 1 Does not include unscheduled visits Reference ranges: Heart rate, 50 to 130 bpm; PR interval, 90 to 200 msec; QRS duration, 40 to 100 msec Abbreviations: EOS = end of study; SPN = viloxazine Table 186 lists the QTcF values for patients in the phase 3 controlled trials whose QTcF increased from normal to >440 msec by EOS. No patient receiving viloxazine ER had a >60 msec increase in QTcF and no patient had a QTc value of >500 msec. The observed changes are unlikely to be clinically meaningful. Of note, the total QT study did not find evidence that

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viloxazine ER prolongs the QT interval. Please see the QT-IRT consultative review for a full discussion of studies evaluating the effect of viloxazine ER on the QT interval. Table 186. Shift from Normal to Prolonged QTcF (> 440) in Viloxazine ER–Exposed Patients (Studies 812P301, 812P302, 812P303, and 812P304) Patient ID Treatment Arm Study Visit QTcF (msec) 303 (b) (6) SPN-812 ER 200 mg Week 8 (EOS) 452 304 SPN-812 ER 400 mg Week 7 (EOS) 441 304 SPN-812 ER 400 mg Week 7 (EOS) 453 304 SPN-812 ER 400 mg Week 7 (EOS) 442 Source: adeg.xpt. Created by the Clinical Data Scientist. Abbreviations: EOS = end of study; ER = extended release

Additional Safety Data—Studies 812P202 and 812P310

Table 187 lists the AEs reported by ≥2% of patients treated with viloxazine ER and that occurred more frequently than in the placebo group in Study 812P202. The AE profile in this phase 2 dose-ranging study was comparable to that in the phase 3 safety and efficacy studies. Table 187. Treatment-Emergent Adverse Events Occurring in ≥2% of Viloxazine-Treated Patients and More Frequently than Placebo (Study 812P202) Total Viloxazine Placebo (N=193) (N=24) Adverse Event n (%) n (%) Somnolence 41 (21) 1 (4) Headache 27 (14) 1 (4) Decreased appetite 24 (12) 2 (8) Vomiting 14 (7) 0 Insomnia 12 (6) 0 Abdominal pain 12 (6) 1 (4) Fatigue 10 (5) 0 Nausea 10 (5) 0 Gastroenteritis 9 (5) 1 (4) Irritability 8 (4) 0 Tachycardia 7 (4) 0 Weight decreased 5 (3) 0 Rash 5 (3) 0 Agitation 5 (3) 0 Dyspepsia 4 (2) 0 Suicidal ideation 4 (2) 0 Sedation 4 (2) 0 Diarrhea 4 (2) 0 Tearfulness 4 (2) 0 Source: adae.xpt. Created by the Clinical Reviewer. Somnolence: somnolence, hypersomnia Headache: headache, migraine, tension headache Vomiting: vomiting, procedural vomiting Abdominal pain: abdominal pain, abdominal pain upper, abdominal discomfort Insomnia: insomnia, initial insomnia, middle insomnia, terminal insomnia, Gastroenteritis: viral gastroenteritis, gastroenteritis, gastrointestinal viral infection Tachycardia: tachycardia, increased heart rate Rash: contact dermatitis, rash, skin exfoliation, urticaria Agitation: agitation, anger The most common AEs in Study 812P310 were upper respiratory infection (12.3%), somnolence/sedation (12.1%), headache (8.8%), decreased appetite (5.8%), fatigue (5.5%), and

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abdominal pain (4.6%), irritability (3.6%), insomnia/poor quality sleep (3.2%), vomiting (2.7%), tachycardia/increased heart rate (2.6%), nausea (2.4%), and suicidal ideation/behavior (2.1%).

Subgroup Analysis of Safety Signals

Table 188 summarizes the adverse event profile in demographic subgroups. The proportion of patients who experienced adverse events was comparable in males and females and across age groups. The proportion of patients experiencing an adverse event was also similar in non- Hispanic and Hispanic patients as well as in white and black patients. AE data in patients from other racial groups are difficult to interpret because of the small number included. Table 188. Adverse Events by Demographic Subgroup, Safety Population (Studies 812P301, 812P302, 812P303, and 812P304) Treatment Placebo N=925 N=463 Characteristic [n/Ns (%)] [n/Ns (%)] Sex, n (%) Male 322/611 (53) 93/285 (33) Female 155/314 (49) 78/178 (44) Age group, years, n (%) 6-9 187/356 (53) 59/175 (34) 10-11 78/166 (47) 35/87 (40) 12-14 139/267 (52) 49/134 (37) 15-17 73/136 (54) 28/67 (42) Race, n (%) American Indian or Alaska 6/6 (100) 4/4 (100) Native Black or African American 180/368 (49) 51/175 (29) Multiple 21/33 (64) 9/19 (47) White 267/515 (52) 105/263 (40) Asian 2/2 (100) 2/2 (100) Native Hawaiian or other 1/1 (100) 0 Pacific Islander Ethnicity, n (%) Hispanic or Latino 129/277 (47) 39/131 (30) Not Hispanic or Latino 347/647 (54) 132/331 (40) Not allowed to ask as per 0 0/1 (0) local regulations Missing 1/1 (100) 0 Source: ad b.xpt, adae.xpt; Software: R Abbreviations: N = number of subjects in the treatment group; n = number of subjects with a given characteristic; Ns = number of subjects in the subgroup

Consultative Review, Interdisciplinary Review Team for Cardiac Safety Studies

Viloxazine ER is not associated with prolongation of the corrected QT interval, but it inhibits the cardiac sodium and potassium channels, which may have implications for patients with underlying cardiac disease. The IRT for Cardiac Safety Studies Consultative Review is excerpted below: The effect of viloxazine was evaluated in two separate studies—1) thorough QT study (Study #812P117) and 2) a single- and multiple- ascending dose study (812P120) by concentration-QT analysis. Although no significant QTc prolongation effect of viloxazine

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18. Mechanism of Action/Drug Resistance Additional Information and Assessment

Not applicable. 19. Other Drug Development Considerations Additional Information

Not applicable. 20. Data Integrity-Related Consults (OSI, Other Inspections)

The Division of Clinical Compliance Evaluation in the Office of Scientific Investigations (OSI) conducted site inspections as described in Section II.10. Please refer to the OSI clinical inspection summary for full details. 21. Labeling Summary of Considerations and Key Additional Information

Overview of Major Labeling Changes

The information below represents significant changes made to the full prescribing information from the Applicant’s proposed label for QELBREE (viloxazine ER). HIGHLIGHTS and TABLE OF CONTENTS were revised for consistency with the full Prescribing Information and to reflect the appropriate established pharmacologic class BOXED WARNING The Applicant’s draft labeling contained a warning about an increased risk of suicidal ideation and advised healthcare professionals to monitor for suicidality, clinical worsening, and unusual changes in behavior. As described in Section II.7.6.2, patients exposed to viloxazine ER were more likely to report suicidal ideation and behavior than patients on placebo. We considered whether viloxazine ER should also carry a boxed warning for suicidal ideation and behavior. Although viloxazine ER does not function as a serotonin reuptake inhibitor, it does have activity at serotonin receptors and has previously been marketed as an antidepressant in Europe. Suicidal ideation and behavior in pediatric patients have been associated with use of serotonergic medications including the serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRI). Of note, all antidepressant medications approved by FDA carry a class warning for increased risk of suicidal ideation and behavior in patients ages 24 years or younger. In addition, atomoxetine, which has a similar mechanism of action as viloxazine ER, also has a boxed warning for increased risk of suicidal ideation in children and adolescents. Given the imbalance of suicidal ideation and behavior events in the viloxazine ER clinical trials;

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or in the literature. The review team recommends a PMR for a single-arm pregnancy study to evaluate the effect of viloxazine ER on pregnancy outcomes.

 Milk-only lactation study: No data are available regarding the presence of viloxazine in animal or human milk, the effect of viloxazine ER on lactation, or the effect of viloxazine ER on breast-fed infants. The review team recommends a PMR for a milk-only lactation study in lactating patients to determine if viloxazine ER is present in breast milk and to assess the milk: plasma ratio and the relative infant dose.

 Safety and efficacy study in patients ages 4 to <6 years: See Section 8.3 for discussion of the agreed Pediatric Study Plan (PSP). The review team recommends a PMR for one safety and efficacy study in patients ages 4 to <6 years.

 Long-term, open-label safety study in patients ages 4 to <6 years: As described in the agreed PSP, the Applicant should conduct a 6-month, open-label safety and tolerability study in patients ages 4 to <6 years who completed the short-term safety and efficacy study.

 Hepatic impairment study: The effect of hepatic impairment on viloxazine ER exposure has not been evaluated. The Applicant has previously indicated that a hepatic impairment study will be conducted in parallel with the adult development program. The review team recommends a PMR to complete this study. 23. Financial Disclosure

Table 190. Covered Clinical Studies: 812P301, 812P302, 812P303, 812P304 Was a list of clinical investigators provided: Yes ☒ No ☐ (Request list from Applicant) Total number of investigators identified: Study 812P301, 34; Study 812P302, 33: Study 812P303, 28; Study 812P304, 29 Number of investigators who are Sponsor employees (including both full-time and part-time employees): None Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): None If there are investigators with disclosable financial interests/arrangements, identify the number of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b), (c) and (f)): Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: N/A Significant payments of other sorts: N/A Proprietary interest in the product tested held by investigator: N/A Significant equity interest held by investigator: N/A Sponsor of covered study: N/A Is an attachment provided with details of the Yes ☐ No ☐ (Request details from disclosable financial interests/arrangements: Applicant) Is a description of the steps taken to minimize Yes ☐ No ☐ (Request information from potential bias provided: Applicant) Number of investigators with certification of due diligence (Form FDA 3454, box 3): N/A Is an attachment provided with the reason: Yes ☐ No ☐ (Request explanation from Applicant) 273 Integrated Review Template, version date 2019/10/16

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24. References

Association, AP, 2013, Diagnostic and Statistical Manual of Mental Disorders, 5th edition: American Psychiatric Association. Becker, HC, 1998, Kindling in alcohol withdrawal, Alcohol Health Res World, 22(1):25-33. Chan, E, JM Fogler, and PG Hammerness, 2016, Treatment of Attention-Deficit/Hyperactivity Disorder in Adolescents: A Systematic Review, JAMA, 315(18):1997-2008. Chang, Z, L Ghirardi, PD Quinn, P Asherson, BM D'Onofrio, and H Larsson, 2019, Risks and Benefits of Attention-Deficit/Hyperactivity Disorder Medication on Behavioral and Neuropsychiatric Outcomes: A Qualitative Review of Pharmacoepidemiology Studies Using Linked Prescription Databases, Biol Psychiatry, 86(5):335-343. Edwards, JG and M Glen-Bott, 1984, Does viloxazine have epileptogenic properties?, J Neurol Neurosurg Psychiatry, 47(9):960-964. Ghadially, FN, 1982, Ultrastructural pathology of the cell and matrix : a text and atlas of physiological and pathological alterations in the fine structure of cellular and extracellular components, Ghadially, F. N., London ;: Butterworths. Greaves, P, 2012, Histopathology of Preclinical Toxicity Studies, 4th edition: Academic Press. Greenwood, D, 1975, Animal pharmacology of viloxazine (Vivalan), Journal of International Medical Research, 3:18-30. Hara, K and RA Harris, 2002, The anesthetic mechanism of urethane: the effects on neurotransmitter-gated ion channels, Anesth Analg, 94(2):313-318, table of contents. London, AS and SD Landes, 2019, Cohort Change in the Prevalence of ADHD Among U.S. Adults: Evidence of a Gender-Specific Historical Period Effect, J Atten Disord:1087054719855689. Medicine, Io, 2012, Epilepsy Across the Spectrum: Promoting Health and Understanding, Washington, DC: The National Academies Press. Molina, BSG, SP Hinshaw, JM Swanson, LE Arnold, B Vitiello, PS Jensen, JN Epstein, B Hoza, L Hechtman, HB Abikoff, GR Elliott, LL Greenhill, JH Newcorn, KC Wells, T Wigal, RD Gibbons, K Hur, PR Houck, and MTAC Group, 2009, The MTA at 8 years: prospective follow- up of children treated for combined-type ADHD in a multisite study, J Am Acad Child Adolesc Psychiatry, 48(5):484-500. Morgan, PL, J Staff, MM Hillemeier, G Farkas, and S Maczuga, 2013, Racial and ethnic disparities in ADHD diagnosis from kindergarten to eighth grade, Pediatrics, 132(1):85-93. Pinder, RM, RN Brogden, TM Speight, and GS Avery, 1977, Viloxazine: a review of its pharmacological properties and therapeutic efficacy in depressive illness, Drugs, 13(6):401-421. Ramtekkar, UP, AM Reiersen, AA Todorov, and RD Todd, 2010, Sex and age differences in attention-deficit/hyperactivity disorder symptoms and diagnoses: implications for DSM-V and ICD-11, J Am Acad Child Adolesc Psychiatry, 49(3):217-228 e211-213.

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Richardson, LR and AG Hogan, 1946, Diet of mother and hydrocephalus in infant rats, Fed Proc, 5(1 Pt 2):238. Simmonds, MA and LL Iversen, 1969, Thermoregulation: effects of environmental temperature on turnover of hypothalamic norepinephrine, Science, 163(3866):473-474. Tatsumi, M, K Groshan, RD Blakely, and E Richelson, 1997, Pharmacological profile of antidepressants and related compounds at human monoamine transporters, Eur J Pharmacol, 340(2-3):249-258. Zablotsky, B and JM Alford, 2020, Racial and Ethnic Differences in the Prevalence of Attention- deficit/Hyperactivity Disorder and Learning Disabilities Among U.S. Children Aged 3-17 Years, NCHS Data Brief, (358):1-8. Zablotsky, B, LI Black, MJ Maenner, LA Schieve, ML Danielson, RH Bitsko, SJ Blumberg, MD Kogan, and CA Boyle, 2019, Prevalence and Trends of Developmental Disabilities among Children in the United States: 2009-2017, Pediatrics, 144(4). Zack, MM and R Kobau, 2017, National and State Estimates of the Numbers of Adults and Children with Active Epilepsy - United States, 2015, MMWR Morb Mortal Wkly Rep, 66(31):821-825.

25. Review Team

Table 191. Reviewers of Interdisciplinary Assessment Role Name(s) Regulatory Project Manager Kofi Ansah, PharmD Nonclinical Reviewer Jia Yao, Ph.D. Nonclinical Team Leader Aisar Atrakchi, Ph.D. Office of Clinical Pharmacology Kofi A. Kumi, Ph.D., Vishnu Sharma, Ph.D. Reviewer(s) Office of Clinical Pharmacology Atul Bhattaram, Ph.D., Luning (Ada) Zhuang, Ph.D. Team Leader(s) Clinical Reviewer Martine Solages, MD Clinical Team Leader Bernard Fischer, MD Statistical Reviewer Semhar Ogbagaber, PhD Statistical Team Leader Peiling Yang, PhD Cross-Disciplinary Team Leader Bernard Fischer, MD Division Director (DP) Tiffany R. Farchione, MD Division Director (OCP) Mehul Mehta, Ph.D. Division Director (OB) Hsien Ming J Hung, PhD Office Director (or designated Eric Bastings, MD signatory authority) DHOT = Division of Hematology Oncology Toxicology OCP = Office of Clinical Pharmacology OB = Office of Biostatistics OHOP = Office of Hematology and Oncology Products

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Table 192. Additional Reviewers of Application Office or Discipline Name(s) OPQ Drug Product Grace Chiou (primary) and Julia Pinto (secondary) Drug Substance Friedrich Burnett (primary) and Donna Christner (secondary) Process & Facilities Yongming Lu (primary) and Jonathan Swoboda (secondary) Biopharmaceutics Leah Falade (primary) and Ta-Chen Wu (secondary) DPMH Peds Ethan Hausman and Shetarra Walker (TL) MHT Catherine Roca and Miriam Dinatale (TL) OPDP Nima Ossareh and Aline Moukhtara (TL) OSI Jenn Sellers and Phillip Kronstein (TL) OSE/DEPI Andrew Mosholder and Kira Leishear (TL) OSE/DMEPA Loretta Holmes and Sevan Kolejian (TL) OSE/DRISK Sangeeta Tandon, Victoria Sammarco and Selena Ready (TL) Other CDS Jen Ginsberg, Salman Hosain and Jinzhong (Jin) Liu CSS Edward (Greg) Hawkins and Chad Reissig DMPP-PLT Susan Redwood and Barbara Fuller (TL) OSE/DPV Jonn Bailey, Robert Levin and Vicky Chan (TL) QT-IRT Girish Bende, Lars Johannesen and Christine Garnett OPQ = Office of Pharmaceutical Quality OPDP = Office of Promotion OSI = Office of Scientific Investigations OSE = Office of Surveillance and Epidemiology DEPI = Division of Epidemiology DMEPA = Division of Medication Error Prevention and Analysis DRISK = Division of Risk Management Table 193. Signatures of Reviewers Sections Authored/ Discipline and Title or Acknowledged/ Role Reviewer Name Office/Division Approved1 Entire Review Clinical Eric Bastings, MD CDER/OND/ON ☐ Authored ☒ Approved

Signatory Authority Signature:

1 Include “IA” for authors who contributed to the Interdisciplinary Assessment. Abbreviations: IA = interdisciplinary assessment; ES, Executive Summary

276 Integrated Review Template, version date 2019/10/16

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Digitally signed by Bernard A. Fischer IV -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 'HSXW\ 'LUHFWRU 6LJQDWXUH Bernard A. Fischer IV -S 0.9.2342.19200300.100.1.1=0014393264, cn=Bernard A. Fischer IV -S Date: 2020.11.06 11:38:48 -05'00'

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Digitally signed by Bernard A. Fischer IV -S &URVV'LVFLSOLQDU\ DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 6LJQDWXUH Bernard A. Fischer IV -S 0.9.2342.19200300.100.1.1=0014393264, cn=Bernard A. Fischer IV -S 7HDP /HDG Date: 2020.11.06 11:39:41 -05'00'

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Digitally signed by Semhar Ogbagaber S DN: c=US, o=U S Government, ou=HHS, ou=FDA, Semhar ou=People, 5HYLHZHU 6LJQDWXUH 0 9 2342 19200300 100 1 1=2000705837, cn=Semhar Ogbagaber S Ogbagaber -S Date: 2020 11 05 15:07:29 05'00' 'LVFLSOLQH DQG 7LWOH RU 6HFWLRQV $XWKRUHG 5HYLHZHU 1DPH 2IILFH'LYLVLRQ 5ROH $FNQRZOHGJHG $SSURYHG ,$     $SSHQGL[   DQG  3KDUPDFRORJ\7R[LFRORJ\ $LVDU $WUDNFKL 21''371 տ $XWKRUHG ܆ &RQWULEXWHG ܈ $SSURYHG Digitally signed by Aisar H. Atrakchi -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, 6XSHUYLVRU 6LJQDWXUH ou=People, 0.9.2342.19200300.100.1.1=1300078962, Aisar H. Atrakchi -S cn=Aisar H. Atrakchi -S Date: 2020.11.05 14:02:31 -05'00'

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Digitally signed by Jia Yao -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 5HYLHZHU 6LJQDWXUH cn=Jia Yao -S, 0.9.2342.19200300.100.1.1=2001626953 Jia Yao -S Date: 2020.11.05 13:34:10 -05'00'

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Digitally signed by Mehul U. Mehta -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, 'LYLVLRQ 'LUHFWRU 6LJQDWXUH ou=People, cn=Mehul U. Mehta -S, Mehul U. Mehta -S 0.9.2342.19200300.100.1.1=1300039057 Date: 2020.11.06 08:03:20 -05'00'

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Digitally signed by Luning Zhuang -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, 7HDP /HDGHU 6LJQDWXUH ou=People, cn=Luning Zhuang -S, Luning Zhuang -S 0.9.2342.19200300.100.1.1=2001341990 Date: 2020.11.06 11:03:20 -05'00'

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Digitally signed by Kofi A. Kumi -S DN: c=US, o=U.S. Government, ou=HHS, 5HYLHZHU 6LJQDWXUH ou=FDA, ou=People, cn=Kofi A. Kumi -S, Kofi A. Kumi -S 0.9.2342.19200300.100.1.1=1300086596 Date: 2020.11.06 09:35:34 -05'00'

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Digitally signed by Venkatesh A. Bhattaram -S Venkatesh A. DN: c=US, o=U.S. Government, ou=HHS, 7HDP /HDGHU 6LJQDWXUH ou=FDA, ou=People, 0.9.2342.19200300.100.1.1=1300212823, cn=Venkatesh A. Bhattaram -S Bhattaram -S Date 2020 11 06 10 27 57 05'00'

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Digitally signed by Vishnu D. Sharma -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 5HYLHZHU 6LJQDWXUH Vishnu D. Sharma -S 0.9.2342.19200300.100.1.1=2002769265, cn=Vishnu D. Sharma -S Date: 2020.11.06 09:52:46 -05'00'

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Digitally signed by Kofi B Ansah S3 DN: c=US o=U S Government ou=HHS ou=FDA ou=People 3URMHFW 0DQDJHU 6LJQDWXUH Kofi B. Ansah -S3 cn=Kofi B Ansah S3 0 9 2342 19200300 100 1 1=1300437219 Date: 2020 11 05 13:29:00 05'00'

Reference ID: 4698714 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

BERNARD A FISCHER 11/06/2020 07:28:22 PM

ERIC P BASTINGS 11/06/2020 07:48:34 PM

Reference ID: 4698714